Substituted indole-O-glucosides

ABSTRACT

Substituted indole-O-glucosides, compositions containing them, and methods of using them, for example for the treatment of diabetes and Syndrome X are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of provisional applications Ser. No.60/579,758, filed 15 Jun. 2004; Ser. No. 60/519,155, filed 12 Nov. 2003;Ser. No. 60/491,523, filed 1 Aug. 2003; and Ser. No. 60/491,534, filed 1Aug. 2003, each of which is incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to substituted indole-O-glucosides, compositionscontaining them, and methods of using them, for example, for thetreatment or prophylaxis of diabetes and Syndrome X.

BACKGROUND OF THE INVENTION

Diabetes is a chronic disorder affecting carbohydrate, fat and proteinmetabolism in animals.

Type I diabetes mellitus, which comprises approximately 10% of alldiabetes cases, was previously referred to as insulin-dependent diabetesmellitus (“IDDM”) or juvenile-onset diabetes. This disease ischaracterized by a progressive loss of insulin secretory function bybeta cells of the pancreas. This characteristic is also shared bynon-idiopathic, or “secondary”, diabetes having its origins inpancreatic disease. Type I diabetes mellitus is associated with thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

Type II diabetes mellitus (non-insulin-dependent diabetes mellitus orNIDDM) is a metabolic disorder involving the dysregulation of glucosemetabolism and impaired insulin sensitivity. Type II diabetes mellitususually develops in adulthood and is associated with the body'sinability to utilize or make sufficient insulin. In addition to theinsulin resistance observed in the target tissues, patients sufferingfrom type II diabetes mellitus have a relative insulin deficiency—thatis, patients have lower than predicted insulin levels for a given plasmaglucose concentration. Type II diabetes mellitus is characterized by thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

Syndrome X, also termed Insulin Resistance Syndrome (IRS), MetabolicSyndrome, or Metabolic Syndrome X, is recognized in some 2% ofdiagnostic coronary catheterizations. Often disabling, it presentssymptoms or risk factors for the development of Type II diabetesmellitus and cardiovascular disease, including impaired glucosetolerance (IGT), impaired fasting glucose (IFG), hyperinsulinemia,insulin resistance, dyslipidemia (e.g., high triglycerides, low HDL),hypertension and obesity.

Therapy for IDDM patients has consistently focused on administration ofexogenous insulin, which may be derived from various sources (e.g.,human, bovine, porcine insulin). The use of heterologous speciesmaterial gives rise to formation of anti-insulin antibodies which haveactivity-limiting effects and result in progressive requirements forlarger doses in order to achieve desired hypoglycemic effects.

Typical treatment of Type II diabetes mellitus focuses on maintainingthe blood glucose level as near to normal as possible with lifestylemodification relating to diet and exercise, and when necessary, thetreatment with anti-diabetic agents, insulin or a combination thereof.NIDDM that cannot be controlled by dietary management is treated withoral antidiabetic agents.

Although insulin resistance is not always treated in all Syndrome Xpatients, those who exhibit a prediabetic state (e.g., IGT, IFG), wherefasting glucose levels may be higher than normal but not at the diabetesdiagnostic criterion, is treated in some countries (e.g., Germany) withmefformin to prevent diabetes. The anti-diabetic agents may be combinedwith pharmacological agents for the treatment of the concomitantco-morbidities (e.g., antihypertensives for hypertension, hypolipidemicagents for lipidemia).

First-line therapies typically include mefformin and sulfonylureas aswell as thiazolidinediones. Metformin monotherapy is a first linechoice, particularly for treating type II diabetic patients who are alsoobese and/or dyslipidemic. Lack of an appropriate response to metforminis often followed by treatment with metformin in combination withsulfonylureas, thiazolidinediones, or insulin. Sulfonylurea monotherapy(including all generations of drugs) is also a common first linetreatment option. Another first line therapy choice may bethiazolidinediones. Alpha glucosidase inhibitors are also used as firstand second line therapies. Patients who do not respond appropriately tooral anti-diabetic monotherapy, are given combinations of theabove-mentioned agents. When glycemic control cannot be maintained withoral antidiabetics alone, insulin therapy is used either as amonotherapy, or in combination with oral antidiabetic agents.

One recent development in treating hyperglycemia is focused on excretionof excessive glucose directly into urine. Specific inhibitors of SGLTshave been shown to increase the excretion of glucose in urine and lowerblood glucose levels in rodent models of IDDM and NIDDM.

SUMMARY OF THE INVENTION

One aspect of the invention is directed to methods and compositions forthe treatment or prophylaxis of diabetes, Syndrome X, or associatedsymptoms or complications. More specifically, this invention is directedto a novel method of treating diabetes or Syndrome X, or associatedsymptoms or complications thereof, in a subject afflicted with such acondition, said method comprising administering one or more glucosereabsorption inhibitors and administering one or more antidiabeticagent(s) for the treatment of diabetes or Syndrome X, or associatedsymptoms or complications thereof.

Another aspect of the invention features compounds of Formula (I):

wherein

-   R₁, is H, C₁₋₄ alkyl, or R₄R₅N—(CO)—; each of R₄ and R₅ is    independently C₁₋₅ alkyl;-   R₂ is H, F, Cl or C₁₋₄ alkyl;-   R₃ is H or C₁₋₄ alkyl, provided that when R₃ is C₁₋₄ alkyl, then R₂    is H;-   Q is —C═O—, or —(CH₂)_(n)— where n=0, 1, or 2;-   P═H, C₁₋₇ acyl, or (C₁₋₆ alkoxy)carbonyl;

Z is substituted or unsubstituted, and is selected from C₃₋₇ cycloalkyl,phenyl, 5- or 6-membered heterocyclyl having 1 or 2 heteroatomsindependently selected from N, O, and S, a biaryl, and a 9- or10-membered fused bicyclyl or fused heterobicyclyl, wherein said fusedheterobicyclyl has between 1 and 4 heteroatoms (and preferably between 1and 2 heteroatoms) independently selected from N, O, and S; or apharmaceutically acceptable salt, thereof.

One aspect of the invention features a pharmaceutical compositioncomprising a glucose reabsorption inhibitor (alone or in combinationwith one or more additional antidiabetic agents), and a pharmaceuticallyacceptable carrier. The invention also provides a process forformulating a pharmaceutical composition, comprising formulatingtogether a glucose reabsorption inhibitor, (optionally with at least oneantidiabetic agent), and a pharmaceutically acceptable carrier.

An embodiment of the invention is a method for treating diabetes orSyndrome X, or associated symptoms or complications thereof in asubject, said method comprising administering to said subject a jointlyeffective amount of a glucose reabsorption inhibitor and administeringto said subject a jointly effective amount of an antidiabetic agent,said combined administration providing the desired therapeutic effect.

Another embodiment of the invention is a method for inhibiting the onsetof diabetes or Syndrome X, or associated symptoms or complicationsthereof in a subject, said method comprising administering to saidsubject a jointly effective dose of a glucose reabsorption inhibitor andadministering to said subject a jointly effective amount of an one ormore antidiabetic agent(s), said combined administration providing thedesired prophylactic effect.

In the disclosed methods, the diabetes or Syndrome X, or associatedsymptoms or complications thereof, is selected from IDDM, NIDDM, IGT,IFG, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis,polycystic ovarian syndrome, hypertension, ischemia, stroke, heartdisease, irritable bowel disorder, inflammation, and cataracts.

Also included in the invention is the use of one or more glucosereabsorption inhibitors in combination with one or more antidiabeticagents for the preparation of a medicament for treating a conditionselected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy,retinopathy, atherosclerosis, polycystic ovarian syndrome, hypertension,ischemia, stroke, heart disease, irritable bowel disorder, inflammation,and cataracts.

DETAILED DESCRIPTION OF THE INVENTION

All diabetics, regardless of their genetic and environmentalbackgrounds, have in common an apparent lack of insulin or inadequateinsulin function. Because transfer of glucose from the blood into muscleand fatty tissue is insulin dependent, diabetics lack the ability toutilize glucose adequately, which leads to undesired accumulation ofglucose in the blood (hyperglycemia). Chronic hyperglycemia leads todecrease in insulin secretion and contributes to increased insulinresistance, and as a result, the blood glucose concentration isincreased so that diabetes is self-exacerbated (Diabetologia, 1985,“Hyperglycaemia as an inducer as well as a consequence of impaired islecell function and insulin resistance: implications for the management ofdiabetes”, Vol. 28, p. 119); Diabetes Cares, 1990, Vol. 13, No. 6,“Glucose Toxicity”, pp. 610–630). Therefore, by treating hyperglycemia,the aforementioned self-exacerbating cycle is interrupted so that theprophylaxis or treatment of diabetes is made possible.

U.S. Pat. No. 6,153,632 to R. Rieveley discloses a method andcomposition stated to be for the treatment of diabetes mellitus (Type I,Impaired Glucose Tolerance [“IGT”] and Type II), which incorporates atherapeutic amount of one or more insulin sensitizers along with one ormore of an orally ingested insulin, an injected insulin, a sulfonylurea,a biguanide or an alpha-glucosidase inhibitor for the treatment ofdiabetes mellitus.

According to one aspect, the invention features the combination of aPPAR modulator, preferably a PPAR δ agonist, and an SGLT inhibitor,preferably an SGLT 2 inhibitor or a selective SGLT 2 inhibitor.

A. Terms

Some terms are defined below and by their usage throughout thisdisclosure.

Unless otherwise noted, “alkyl” and “alkoxy” as used herein, whetherused alone or as part of a substituent group, include straight, cyclic,and branched-chain alkyl having 1 to 8 carbon atoms, or any numberwithin this range. For example, alkyl radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 2-butenyl,2-butynyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl,neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals areoxygen ethers formed from the previously described straight or branchedchain alkyl groups. The alkyl and alkoxy group may be independentlysubstituted with one to five, preferably one to three groups selectedfrom halogen (F, Cl, Br, I), oxo, OH, amino, carboxyl, and alkoxy. Thealkyl and alkoxy group may also be independently linked to one or morePEG radicals (polyethylene glycol).

The term “acyl” as used herein, whether used alone or as part of asubstituent group, means an organic radical having a carbonyl grouplinked to hydrocarbyl group having 1 to 7 carbon atoms (branched orstraight chain or cyclic) derived from an organic acid by removal of thehydroxyl group. For example C₄ acyl can include (CO)CH₂CH₂CH₂CH₃ and(CO)(CH₂(CH) (CH₃)₂; similarly, C₆ acyl includes both (CO)(C₆H₁₃) and(CO)(C₆H₅). The term “Ac” as used herein, whether used alone or as partof a substituent group, means acetyl.

“Aryl” is a carbocyclic aromatic radical including, but not limited to,phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radicalmay be substituted by independent replacement of 1 to 3 of the hydrogenatoms thereon with halogen, OH, CN, mercapto, nitro, amino, cyano,optionally substituted C₁–C₈-alkyl, optionally substituted alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino,di(C₁–C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—. Illustrative aryl radicals include, for example, phenyl,naphthyl, biphenyl, indene

indane

fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl,carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl,hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl,acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph”or “PH” denotes phenyl.

The term “heteroaryl” as used herein represents a stable five orsix-membered monocyclic or bicyclic aromatic ring system which consistsof carbon atoms and from one to three heteroatoms selected from N, O andS. The heteroaryl group may be attached at any heteroatom or carbonatom, which results in the creation of a stable structure. Examples ofheteroaryl groups include, but are not limited to benzofuranyl,benzothiophenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl,benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl or quinolinyl. Prefered heteroaryl groups includepyridinyl, thiophenyl, furanyl, and quinolinyl. When the heteroarylgroup is substituted, the heteroaryl group may have one to threesubstituents which are independently selected from halogen, OH, CN,mercapto, nitro, amino, cyano, optionally substituted C₁–C₈-alkyl,optionally substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkyl-amino, di(C₁–C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—.

The terms “heterocycle,” “heterocyclic,” and “heterocyclyl” refer to anoptionally substituted, fully or partially saturated, aromatic ornonaromatic, cyclic group which is, for example, a 4- to 7-memberedmonocyclic, 7- to 11-membered (or 9–10 membered) bicyclic(heterobicyclyl), or 10- to 15-membered tricyclic ring system, which hasat least one heteroatom in at least one carbon atom containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, andsulfur atoms, where the nitrogen and sulfur heteroatoms may alsooptionally be oxidized. The nitrogen atoms may optionally bequaternized. The heterocyclic group may be attached at any heteroatom orcarbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl;pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl;isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl;piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl;2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl;tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl;thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone;1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; and the like. Exemplarybicyclic heterocyclic groups (or heterobicyclyls) include quinuclidinyl;tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl;dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone;dihydrobenzopyranyl; indolinyl; isochromanyl; benzimidazolyl;benzthiazolyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and thelike. When the heteroaryl group is substituted, the heterocyclyl may beindependently substituted with one to five, preferably one to threegroups selected from halogen, OH, CN, mercapto, nitro, amino, cyano,optionally substituted C₁–C₈-alkyl, optionally substituted alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino,di(C₁–C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—.

The term “biaryl” includes a heteroaryl linked to a phenyl, a phenyllinked to a heteroaryl (such as furan, pyridine, or thiophene ), and aphenyl linked to a phenyl. Examples of phenyl-phenyl, heteroaryl-phenyl,heteroaryl-phenyl, and , phenyl-heteroaryl, respectively, include:

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “combined administration” includes co-administrationwherein: 1) the two or more agents are administered to a subject atsubstantially similar times; and 2) the two or more agents areadministered to a subject at different times, at independent intervalswhich may or may not overlap or coincide.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is the object of treatment,observation or experiment.

The term “RXR modulator” as used herein, refers to Retinoid-X receptoragonists, partial agonists, or antagonists. Preferably the modulatorincreases insulin sensitivity. According to one aspect, the modulator isan RXR agonist.

Diabetes, Syndrome X, and associated symptoms or complications includesuch conditions as IDDM, NIDDM, IGT, IFG, obesity, nephropathy,neuropathy, retinopathy, atherosclerosis, polycystic ovarian syndrome,hypertension, ischemia, stroke, heart disease, irritable bowel disorder,inflammation, and cataracts. Examples of a prediabetic state includesIGT and IFG.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated by the modulation of glucosereabsorption activity or other antidiabetic activity (such as RXRactivity) or both. Thus, the present invention provides combinations oftwo or more drugs wherein, for example, (a) each drug is administered inan independently therapeutically or prophylactically effective amount;(b) at least one drug in the combination is administered in an amountthat is sub-therapeutic or sub-prophylactic if administered alone, butis therapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

The term “protecting groups” refer to those moieties known in the artthat are used to mask functional groups; protecting groups may beremoved during subsequent synthetic transformations or by metabolic orother in vivo administration conditions. During any of the processes forpreparation of the compounds of the present invention, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973;and T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, 1999. The protecting groupsmay be removed at a convenient subsequent stage using methods known inthe art. Examples of hydroxyl and diol protecting groups are providedbelow.

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, and polyethyleneglycol ethers.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(/midazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate), and polyethyleneglycol esters.

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, methyldithiocarbonate, and polyethyleneglycol carbonates.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(meyslate),benzylsulfonate, and tosylate.

Protection for 1,2- and 1,3-Diols

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include methylene, ethylidene,1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene,2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene,cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene,2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and2-nitrobenzylidene.

Cyclic Ortho Esters

Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Silyl Derivatives

Examples of silyl derivatives include di-t-butylsilylene group, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

Glucose Reabsorption Inhibitors

One method of treating hyperglycemia is to excrete excessive glucosedirectly into urine so that the blood glucose concentration isnormalized. For example, sodium-glucose cotransporters (SGLTs),primarily found in chorionic membrane of the intestine and the kidney,are a family of proteins actively involved in the normal process ofglucose absorption. Among them, SGLT1 is present in intestinal and renalepithelial cells (Lee et al., 1994), whereas SGLT2 is found in theepithelium of the kidney (You et al., 1995, MacKenzie et al., 1994).Glucose absorption in the intestine is primarily mediated by SGLT1, ahigh-affinity low-capacity transporter with a Na⁺:glucose transportratio of 2:1. SGLT2, also known as SAAT1, transports Na⁺ and glucose ata ratio of 1:1 and functions as a low-affinity high-capacitytransporter. These SGLTs are characterized in Table 1:

TABLE 1 Preferred K_(m)* TmG** K_(m)* ISOFORM TISSUE StoichiometrySubstrate in vitro in vitro In vivo SGLT1 Sm. Intestine 2:1 D-glucose0.1 nd Nd D-galactose Kidney (S1, S3) 2:1 D-glucose 0.39 7.9 0.3D-galactose SGLT2 Kidney (S3) 1:1 D-glucose 1.64 83 6 (SAAT1) *(mM) forD-glucose **Maximal transport rate pmol/min/mm

Renal reabsorption of glucose is mediated by SGLT1 and SGLT2 (Silvermanet al., 1992; Deetjen et al., 1995). Plasma glucose is filtered in theglomerulus and is transepithelially reabsorbed in the proximal tubules.SGLT1 and SGLT2 are located in the apical plasma membranes of theepithelium and derive their energy from the inward sodium gradientcreated by the Na⁺/K⁺ ATPase pumps located on the basolateral membrane.Once reabsorbed, the elevated cytosolic glucose is then transported tothe interstitial space by facilitated glucose transports (GLUT1 andGLUT2). Therefore, inhibition of SGLTs reduces plasma glucose throughsuppression of glucose reabsorption in the kidney. A therapeutically orprophylactically effective amount of an SGLT inhibitor, such as thatsufficient to increase urine glucose excretion, or to decrease plasmaglucose, in a subject by a desired amount per day, can be readilydetermined using methods established in the art. Recently, it has beenfound that phlorizin, a natural glycoside present in barks and stems ofRosaceae (e.g., apple, pear, etc.), inhibits Na⁺-glucose co-transporterslocated in chorionic membrane of the intestine and the kidney. Byinhibiting Na⁺-glucose co-transporter activity, phlorizin inhibits therenal tubular glucose reabsorption and promotes the excretion of glucoseso that the glucose level in a plasma is controlled at a normal levelfor a long time via subcutaneous daily administration (Journal ofClinical Investigation, 1987, Vol. 79, p. 1510).

Other SGLT inhibitors include alkyl- and phenyl-glucosides,1-5-isoquinolinesulfonyl)-2-methylpiperazine-HCl (indirectly via proteinkinase C), p-chloromercuribenzoate (PCMB), N,N′-dicyclohexylcarbodiimide(DCCD), copper and cadmium ions, and trivalent lanthanides.

B. Compounds

The invention features compounds of Formula (I):

wherein

-   R₁ is H, C₁₋₄ alkyl, or R₄R₅N—(CO)—; each of R₄ and R₅ is    independently C₁₋₅ alkyl;-   R₂ is H, F, Cl or C₁₋₄ alkyl;-   R₃ is H or C₁₋₄ alkyl, provided that where R₃ is C₁₋₄ alkyl, then R₂    is H;-   Q is —C═O—, or —(CH₂)_(n)— where n=0, 1, or 2;-   P═H, C₁₋₇ acyl, or (C₁₋₆ alkoxy)carbonyl; and-   Z is substituted or unsubstituted, and is selected from C₃₋₇    cycloalkyl, phenyl, 5- or 6-membered heterocyclic having 1 or 2    heteroatoms independently selected from N, O, and S, a 9- or    10-membered fused bicyclyl (such as naphthyl), or fused    heterobicyclyl, wherein the fused heterobicyclyl has between 1 and 4    heteroatoms (and preferably between 1 and 2 heteroatoms)    independently selected from N, O, and S.

Examples of compounds of Formula (I) include those wherein: (a) R₁ is H;(b) R₂ is H, methyl, or ethyl; (c) Q is —(CH₂)_(n)— and n is 1 or 2; (d)Z is unsubstituted or independently substituted with between 1 and 3substituents independently selected from C₁₋₄ alkoxy, phenoxy, C₁₋₄alkyl, C₃₋₆ cycloalkyl, halo, hydroxy, cyano, amino, C₁₋₄ alkylthio,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl, C₁₋₄ aminoalkyl, mono anddi-(C₁₋₄ alkyl)amino, phenyl, C₁₋₄ alkylaminosulfonyl (SO₂NHR),amino-(C₁₋₄ alkylsulfonyl) (NHSO₂R), C₁₋₄ dialkylaminosulfinyl (SONHRR),C₁₋₄ alkylamido (NHCOR), C₁₋₄ alkylcarbamido (CONHR), 5–6 memberedheterocyclyl containing between 1 and 3 heteroatoms independentlyselected from N, S, and O; and wherein the substituent(s) on Z can befurther independently substituted with between 1 and 3 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ alkyl, halo, hydroxy,cyano, amino, mono or di-(C₁₋₄ alkyl)amino and C₁₋₄ alkylthio; (e) Z is4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substitutedor unsubstituted thiophene, biaryl, benzofuranyl, dihydrobenzofuranyl,4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl,indanyl, or naphthyl; (f) Z is unsubstituted or substituted with between1 and 2 substituents independently selected from methoxy, ethoxy,fluoro, chloro, methyl, ethyl, propyl, butyl and isopropyl; (g) Z isbiphenyl, 4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl,2-(5-phenyl)thiophenyl, 4-(1H-pyrazol-1-yl)phenyl, (4-ethyl)phenyl,(4-propyl)phenyl, (4-methoxy)phenyl, dihydrobenzofuran-5-yl, ordihydrobenzofuran-6-yl; (h) R₁ is H; and R₂ is H, methyl, ethyl, propyl,or isopropyl; (h) Q is —(CH₂)_(n)—; n is 1 or 2; and R₂ is H, methyl orethyl; (i); P is H, C₁₋₃ acyl, or (C₁₋₃ alkoxy)carbonyl; (j)R₁ is H; R₂is H, methyl, or ethyl; Q is —(CH₂)_(n)— and n is 1 or 2; and Z is4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substitutedor unsubstituted thiophene, biaryl, benzofuranyl, dihydrobenzofuranyl,4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl,indanyl, ornaphthyl; (k) R₁ is H; R₂ is H, methyl, or ethyl; wherein Zis 4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl,substituted or unsubstituted thiophene, biaryl, benzofuranyl,dihydrobenzofuranyl, 4-substituted pyridyl, benzo[b]thienyl, chromanyl,benzothiophenyl, indanyl, or naphthyl; and Z is unsubstituted orsubstituted with between 1 and 2 substituents independently selectedfrom methoxy, ethoxy, fluoro, chloro, methyl, ethyl, propyl, butyl andisopropyl; (I) and combinations of the above.

Preferred examples include:2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1-methyl-1H-indol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Methoxy-phenyl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-methoxycarbonyl-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-hexanoyl-β-D-glucopyranoside;2-[3-(4-Methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-(3-Biphenyl-4-ylmethyl-1H-indol-4-yloxy)-β-D-glucopyranoside;2-[3-(4-Ethoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methylsulfanyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside; and2-[3-(4-Pyridin-3-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside.

Further examples of preferred compounds include:2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-6-O-acetyl-β-D-glucopyranoside;2-[3-(2-Benzo[1,3]dioxol-5-yl-ethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[3-(2-Naphthalen-2-yl-ethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(4-Ethoxy-phenyl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Methoxy-phenyl)-ethyl]-6-methyl-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[3-(3-Fluoro-4-methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Propyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Isopropyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(2-Fluoro-biphenyl-4-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(3-Fluoro-4-methoxy-benzyl)-1H-indol-4-yloxy]-D-glucopyranoside;2-[3-(4-Phenoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Chloro-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-(3-Naphthalen-2-ylmethyl-1H-indol-4-yloxy)-β-D-glucopyranoside and2-[3-(4-Ethyl-benzyl)-2-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside.

Additional examples of compounds of the invention include:2-{3-[2-(4-Ethyl-phenyl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[1-Diethylcarbamoyl-3-(4-methoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methoxy-benzyl)-1-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1-isopropyl-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-Methyl-2-thienyl(-1H-indol-4-yloxy)-β-D-glucopyranoside;2-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranosideand 2-[3-(4-Ethylbenzoyl)-1H-indol-4-yloxy]-β-D-glucopyranoside and2-[3-(4-Methoxy-phenyl)-1H-indol-4-yloxy]-β-D-glucopyranoside.

Additional examples include:2-[3-(4-Cyclopropyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside,2-[3-(4-Pyrazol-1-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside,2-[6-Chloro-3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside,2-[3-(4-Ethyl-benzyl)-6-fluoro-1H-indol-4-yloxy]-β-D-glucopyranoside,2-[3-(5-Ethyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside,2-[3-(5-Propyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranosideand2-[3-(5-Phenyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside.

The more preferred compounds include:2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1-methyl-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[3-(3-Fluoro-4-methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methylsulfanyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-methoxycarbonyl-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-β-D-glucopyranoside;2-[3-(4-Propyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-(3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy)-β-D-glucopyranoside;2-[3-(4-Cyclopropyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Pyrazol-1-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside,2-[6-Chloro-3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-fluoro-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(5-Ethyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranosideand2-[3-(5-Phenyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside.

The most preferred compounds are2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-β-D-glucopyranosideand 2-(3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy)-β-D-glucopyranoside.

C. Synthetic Methods.

The compounds of the invention can be made according to traditionalorganic synthesis methods as well as according to combinatorial ormatrix synthesis methods. The following three schemes and chemicalExamples 1–38 provide general guidance.

Compounds of this invention where R₃ is H and Z is aromatic ring can beprepared as outlined in Schemes 1 and 3. Compounds of formula 1 where R₂is any group other than hydrogen defined in Claim 1 can be prepared fromcommercially available or readily prepared 4-substituted2-hydroxybenzaldehyde [Acta Chem. Scand. 1999, 53, 258; WO 2003043621]as described by Fresneda et.al. [Tetrahedron 2001, 57, 2355–2363].

Compounds of formula 2 where P₁ is benzyl or methyl and P₂ isbenzenesulfonyl can be prepared by iodination of commercially available4-benzyloxyindole or 4-methoxyindole or compounds of formula 1 where R₂is any group other than hydrogen defined in Claim 1 using chloroiodidein the presence of a base, such as pyridine, in dichloromethane followedby protection of the indole nitrogen with benzenesulfonyl group.

Compounds of formula 3 can be obtained by coupling compounds of formula2 with selected aryl or heteroaryl boronic acids under known Suzukicoupling reaction conditions [Miyaura,N.; Suzuki, A.; Chem. Rev. 1995,95, 2457–2483]. Compounds of formula 3 wherein Z is biaryl can beprepared by either coupling commercially available biarylboronic acidsor through two consecutive coupling reactions. The first couplingreaction adds commercially available 4-chlorophenylboronic acid followedby the addition of a second aryl or heteroaryl boronic acid under Suzukireaction conditions.

The indole nitrogen of compounds of formula 3 can be deprotected with abase, such as potassium hydroxide, in refluxing ethanol to providecompounds of formula 5. The sodium salt of 5 is treated with an alkylhalide to give the N-alkylated (R₁) product followed by palladiumcatalyzed hydrogenation at 10–30 psi of hydrogen pressure to providecompounds of formula 6.

A compound of formula 2 can also be treated with ethylmagnesium bromideat 0° C. in dry THF followed by addition of an aryl carboxaldehyde togive an indolecarbinaol. The crude indolecarbinol can be reduced withtriethylsilane and stannic chloride in dichloromethane at −78° C. toprovide compounds of formula 9, wherein n is 1.

The phenol protecting groups of compounds of formula 3 or 9 can beremoved with boron tribromide at −78° C. in a chlorinated solvent whenP₁ is methyl or under catalytic hydrogenation conditions at H₂ pressuresranging from 10–40 psi when P₁ is benzyl to obtain compounds of formula4 or 10.

Compounds of this invention where n is 1 or 2 can be prepared asoutlined in Schemes 2 and 3. Compounds of formula 1 wherein R₂ ishydrogen and R₃ is any group other than hydrogen defined in Claim 1 canbe prepared from 3-amino-o-cresol or 2-methyl-3-phenylmethoxy aniline[Pitzele, et. al. EP 155635, 1985] as described by Dillard et, al. [J.Med. Chem. 1996, 39, 5119–5136].

Compounds of formula 7 wherein P₁ is benzyl can be prepared byformylation of compounds of the formula 1 with phosphorus oxychlorideunder known reaction conditions. The indole nitrogen of synthesizedcompounds of formula 7 or commercially available4-benzyloxy-1H-indole-3-carboxaldehyde can be protected by treatmentwith either di-tert-butyl dicarbonate or N,N-diethylcarbamyl chloride togive compounds of formula 8. These protected indoles may be treated withylides under standard Wittig reaction conditions to provide an E/Zmixture of compounds. Reduction of the alkene provides compounds offormula 9, wherein n is 2.

A compound of formula 8 can also be treated with an aryl magnesiumbromide in THF to give an indolecarbinol. The crude indolecarbinol canbe reduced with triethylsilane and stannic chloride in dichloromethaneat −78° C. to provide compounds of formula 9, wherein n is 1.

Alternatively compounds of formula 1 where R₂ and P₁ are methyl and R₃is hydrogen or commercially available 4-methoxyindole can be treatedwith substituted benzoyl chlorides using standard Friedel-Craftacylation conditions followed by protection of the indole nitrogen withbenzenesulfonyl chloride to provide compounds of formula 11. Furtherreduction with sodium borohydride in the presence of trifluoroaceticacid in a chlorinated solvent can provide compounds of formula 9.Compounds of formula 11 wherein Z is 4-bromophenyl can be furthercoupled with substituted aryl or heteroaryl boronic acids under standardSuzuki reaction conditions to provide the biaryl analogs.

The phenol protecting groups of compounds of formula 9 or 11 can beremoved with boron tribromide at −78° C. in a chlorinated solvent whenP₁ is methyl or under catalytic hydrogenation conditions at H₂ pressuresranging from 10–40 psi when P₁ is benzyl to obtain compounds of formula10 or 14.

The indole nitrogen of compounds of formula 9 can be deprotected bytreatment with trifluoroacetic acid in a chlorinated solvent at 0° C. toremove the BOC group or by treatment with an aqueous base such as sodiumhydroxide to remove the N,N-diethylcarbamyl group to yield compounds offormula 12. Further alkylation of the indole nitrogen followed bydeprotection of the phenol group as previously described providescompounds of formula 13.

Alternatively, a compound of formula 12 wherein n is 1 and R₃ is anygroup other than hydrogen can be obtained directly from a compound offormula 1 and an aromatic aldehyde in the presence of triethylsilane andtrifluoroacetic acid in dichloromethane at 0° C. [Appleton, J. E., et.al., Tetrahedron Letter, 1993, 34, 1529].

Compounds of formula 17, wherein Q and Z are defined in Claim 1 and R₁is hydrogen, can be obtained from compounds of formula 15 (which isformula 4 wherein Q is absent, or formula 10 wherein Q is (CH₂)_(n) andn is 1 or 2, or formula 14, wherein Q is C═O), prepared in Schemes 1 or2, by glycosidation of the phenol group with2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in an appropriatesolvent, such as acetone, acetonitrile or DMF, under basic conditions,such as potassium carbonate or lithium carbonate. Deprotection of theindole nitrogen and acetyl groups can be done in one step with a basesuch as potassium hydroxide or sodium hydroxide in refluxing ethanol toprovide compounds of formula 18, wherein P is H.

Compounds of formula 18, wherein Q and Z are defined in Claim 1, P is Hand R₁ is either H or any group other than hydrogen, can be obtainedfrom compounds of formula 16 (which is formula 6 wherein Q is absent, orformula 13 wherein Q is (CH₂)_(n) and n is 1 or 2), prepared in Schemes1 and 2, by glycosidation of the phenol group as described abovefollowed by deprotection in an alcoholic solvent such as methanol usingmild basic conditions, such as potassium carbonate or sodium methoxide,at room temperature.

Compounds of formula 18, wherein P is H, can be treated with oneequivalent of alkyl chloroformate or alkyl acid chloride in collidine toselectively acylate the 6-OH group of the glucose to provide compoundsof formula 18, wherein P is acyl or alkoxycarbonyl groups.

D. Additional Antidiabetic Agents

Antidiabetic agents that can be used, according to the invention, as asecond or a third antidiabetic agent in a pharmaceutical composition,formulation, or combination method of treatment (regimen) include, butare not limited to those in Table 2.

TABLE 2 Combination Therapies with SGLT Inhibitors Mechanism or ClassDrug/Compound Biguanide (class) metformin Fortamet (metformin XT)metformin GR metformin XL NN-414 fenofibrate/metformin combo InsulinSecretagogue glimeparide (mech), Sulfonylureas (class)glyburide/glibenclamide combo glyburide/metformin combo glipizideglipizide/metformin combo gliclazide chlorpropamide tolbutamidetolazamide Insulin Secretagogue repaglinide (mech), Meglitinides (class)nateglinide mitiglinide Alpha-glucosidase acarbose inhibitors (mech)miglitol voglibose emiglitate Insulin and Insulin insulin lisproanalogues (class) insulin glargine insulin detemir insulin glulisineinsulin aspart human insulin (Humulin R) human insulin (Novolin R humaninsulin (Novolin BR) insulin, zinc suspension (Humulin L) insulin NHP(Humulin N) insulin, zinc suspension (Novolin L) insulin NHP (Novolin N)insulin, zinc suspension (Humulin U) human insulin, regular and NHP mix(Humulin 50/50) human insulin, regular and NHP mix (Humulin 70/30) humaninsulin, regular and NHP mix (Novolin 70/30) Inhaled insulin (class)Exubera AERx Insulin Diabetes Management System AIR inhaled insulin Oralinsulin (class) Oralin PPARgamma (mech) rosiglitazonerosiglitazone/metformin combo pioglitazone isaglitazone (netoglitazone,MCC-555) rosiglitazone/sulfonylurea ragaglitazar balaglitazone (NN-2344)R-483 rivoglitazone (CS-011) FK-614 SCD-DKY tesaglitazar T131 CLX0921LY-293111 (VML-295) MBX 102 AA10090 CDDO (TP-155C) DRF-2189 PHT-46farglitazar GW-7845 L-764406 NC-2100 PN 2022 (PN 2034) PPARalpha/gammadual MK767/MK0767 (KRP 297) agonists (mech) muraglitazar (BMS-298585)tesaglitazar LY-818 oxeglitazar (EML-4156) LY-929 BVT-142 DRF-2655DRF-4832 DRF-4158 LY-465608 KT6-207 LSN-862 PPARalpha Agonist (mech)Fenofibrate Gemfibrozil Clofibrate Ciprofibrate Benzafibrate K-111LY518674 (LY674) KRP-101 NS-220 GW-9578 GW-7647 GW-9820 LF-200337ST-1929 Wy-14643 PPARdelta Agonist (mech) GW501516 GW-1514 L-165041 GW8547 PPARalpha/delta Dual GW-2433 Agonist (mech) PPARgamma/delta Dualnone in the last PPAR CEA Agonist (mech) PPARalpha/gamma/delta CLX-0940Modulator (mech) RXR Agonist (mech) Insulin Seretagogue Exanatideinjectable (mech), GLP-1 analogue (class) Exanatide LAR injectableExanantide oral Liraglutide GLP-1 agonist (mech) exenatide (AC2993)liraglutide (NN2211) LY-307161 CJC-113 ZP10 GLP-1 BIM-51077 DPPIVInhibitor (mech) LAF-237 P32/98 P93/01 NVP-728 Lipase Inhibitor (mech)Orlistat ATL962 Glucokinase Activator Ro 28–1675 (mech) Ro 27–4375beta-3 Agonist (mech) LY-337604 L-796568 CP-331684 CP-331679 CP-114271Rafabegron (TAK-677) YM-178 N5984 GW427353 IBAT Inhibitor (mech)AZD-7806 SC-990 SC-017 GW-264 HM74a/HM74 Agonist Acipimox (mech)Glucocorticoid A348441 Antagonist (mech) A362947 CP394531 CP409069CP472555 Glycogen Phosphorylase a NN4201 Inhibitor (mech) Ingliforib(CP368296) FXR Antagonist (mech) GW-4064 LXR Agonist (mech) GW-3965T-0901317 T-0314407 FXR Antagonist (mech) GLP-1 Analogue (class) AlbugonGSK-3beta Inhibitor (mech) PTP-1b Inhibitor (mech) ISIS-113715 KP102Amylin Receptor Agonist Pramlintide (symlin/amylin) NO Scavenger (mech)NOX-700 11beta-Hydroxysteroid BVT-3498 Dehydrogenase Inhibitor PeptideYY hormone AC162325 Glucagon Antagonist NN-2501 (mech) PEPCK Inhibitor(mech) R1438 Somatotropin Release- SOM230 inhibiting Factor (mech) CPT-1Inhibitor (mech) ST1326 Carboxypeptidase MLN-4760 Inhibitor (mech)Leptin analogue (class) MetrileptinE. Combinations

The invention features a combination therapy comprising administering aglucose reabsorption inhibitor, such as an SGLT inhibitor, and at leastone antidiabetic agent for the treatment of diabetes or Syndrome X, orassociated symptoms or complications thereof. The demonstrated efficacyof SGLT inhibitors in numerous models of NIDDM validates the utility ofthis drug alone for the treatment of NIDDM in humans. Since glucosereabsorption inhibitors have a mechanism of action distinct from that ofother antidiabetic agents, such as RXR modulators, the disclosedcombination may have the advantage of reducing the amount of either drugnecessary to achieve combined therapeutic or pharmaceutical efficacy,relative to the use of either drug alone, thereby reducing one or moreadverse side-effects, which often include weight gain, edema, cardiachypertrophy, hepatohypertrophy, hypoglycemia, or hepatotoxicity, or anycombination thereof.

The invention provides a method for treating diabetes or Syndrome X, orcomplications thereof in a subject, said method comprising administeringto said subject a jointly effective amount of a glucose reabsorptioninhibitor in combination with a jointly effective amount of anantidiabetic agent. In one aspect of the invention, antidiabetic agentis an RXR agonist or antagonist that increases insulin sensitivity inthe subject. Methods to determine the insulin sensitizing activity of anagent are well known in the art. For example, an insulin sensitizer canincrease glucose tolerance in a subject in an oral glucose tolerancetest.

Particularly, the diabetes or Syndrome X, or associated symptoms orcomplication thereof is selected from IDDM, NIDDM, IGT, and IFG.

In particular, the glucose reabsorption inhibitor is a SGLT1 and/orSGLT2 inhibitor. More particularly, the glucose reabsorption inhibitoris selected from a compound of Formula (III) and a derivative thereof.

For use in medicine, the salt or salts of the compounds of Formula (III)refer to non-toxic “pharmaceutically acceptable salt or salts.” Othersalts may, however, be useful in the preparation of compounds accordingto this invention or of their pharmaceutically acceptable salts.Representative organic or inorganic acids include, but are not limitedto, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric,phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic,fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representativebasic/cationic salts include, but are not limited to, benzathine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine,procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, orzinc. The compounds of Formula (III) or a pharmaceutically acceptablesalt thereof, may include an intramolecular salt thereof, or a solvateor hydrate thereof.

F. Administration, Formulation, and Dosages

The utility of the disclosed compounds, compositions, and combinationsto treat disorders in glucose and lipid metabolism can be determinedaccording to the procedures well known in the art (see the referenceslisted below), as well as all the procedures described in U.S. Pat. Nos.5,424,406, 5,731,292, 5,767,094, 5,830,873, 6,048,842, WO 01/16122 andWO 01/16123 which are incorporated herein by reference. The compound maybe administered to a patient by any conventional route ofadministration, including, but not limited to, intravenous, oral,subcutaneous, intramuscular, intradermal and parenteral administration.Preferably, formulations are for oral administration.

The present invention also provides pharmaceutical compositionscomprising one or more glucose reabsorption inhibitors and one or moreantidiabetic agents in association with a pharmaceutically acceptablecarrier.

The daily dosage of the products may be varied over a wide range from 1to 1000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 2 times per day. The dosages,however, may be varied depending upon the requirement of the patients,the severity of the condition being treated and the compound beingemployed. The use of either daily administration or post-periodic dosingmay be employed. Preferably these compositions are in unit dosage formssuch as tablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, auto-injector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient oringredients are mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of one ormore glucose reabsorption inhibitors and one or more antidiabeticagents, or a pharmaceutically acceptable salt thereof. When referring tothese preformulation compositions as homogeneous, it is meant that theactive ingredient or ingredients are dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient or ingredients of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of material can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also include thesynthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

Advantageously, the combinations of one or more glucose reabsorptioninhibitors of the present invention may be administered, alone or incombination with one or more antidiabetic agents, in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three or four times daily. Furthermore, one or more glucosereabsorption inhibitors and/or one or more antidiabetic agents accordingto the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

Wherein the present invention is directed to the administration of acombination, the compounds may be co-administered simultaneously,sequentially, or in a single pharmaceutical composition. Where thecompounds are administered separately, the number of dosages of eachcompound given per day, may not necessarily be the same, e.g. where onecompound may have a greater duration of activity, and will therefore, beadministered less frequently.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, thestrength of the preparation, the mode of administration, and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient age,weight, diet and time of administration, will result in the need toadjust dosages.

The novel compositions of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of lipids, including but notlimited to amphipathic lipids such as phosphatidylcholines,sphingomyelins, phosphatidylethanolamines, phophatidylcholines,cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidicacids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyldimethylammonium propanes, and stearylamine, neutral lipids such astriglycerides, and combinations thereof. They may either containcholesterol or may be cholesterol-free.

From Formula (I) and other disclosed formulae it is evident that somecompounds in the compositions of the invention may have one or moreasymmetric carbon atoms in their structure. It is intended that thepresent invention include within its scope the stereochemically pureisomeric forms of the compounds as well as their racemates.Stereochemically pure isomeric forms may be obtained by the applicationof art known principles. Diastereoisomers may be separated by physicalseparation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diastereomeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereospecificreactions.

Some compounds in the compositions of the present invention may havevarious individual isomers, such as trans and cis, and various alpha andbeta attachments (below and above the plane of the drawing). Inaddition, where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared as a single stereoisomeror in racemic form as a mixture of some possible stereoisomers. Thenon-racemic forms may be obtained by either synthesis or resolution. Thecompounds may, for example, be resolved into their componentsenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation. The compounds may also beresolved by covalent linkage to a chiral auxiliary, followed bychromatographic separation and/or crystallographic separation, andremoval of the chiral auxiliary. Alternatively, the compounds may beresolved using chiral chromatography. Unless otherwise noted, the scopeof the present invention is intended to cover all such isomers orstereoisomers per se, as well as mixtures of cis and trans isomers,mixtures of diastereomers and racemic mixtures of enantiomers (opticalisomers) as well.

The therapeutic effect of the glucose reabsorption inhibitoradministered in combination with an antidiabetic agent in treatingdiabetes, Syndrome X, or associated symptoms or complications can beshown by methods known in the art. The following examples of combinationtreatment with SGLT inhibitors and antidiabetic agents are intended toillustrate the invention but not to limit it.

G. Synthetic Chemical Examples.

One aspect of the invention features compounds of formula (I) asdescribed above in the Summary section, the description, and theappended claims. These disclosed compounds may be made according totraditional synthetic organic chemistry methods or according to matrixor combinatorial chemistry methods. The Schemes and Examples belowprovide general guidance.

¹HNMR spectra were measured on a Brucker AC-300 (300 MHz) spectrometerusing tetramethylsilane (TMS) as an internal standard.

EXAMPLE 12-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}β-D-glucopyranoside

-   A. 4-Benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide. To a    suspension of sodium hydride (1.52 g, 38 mmol) in anhydrous THF (48    mL) was added dropwise a solution of    4-benzyloxy-1H-indole-3-carbaldehyde (7.93 g, 32 mmol) in anhydrous    THF (80 ml) at 0° C. After stirring at 0° C. for 15 min,    N,N-diethylcarbamyl chloride (4.76 mL, 38 mmol) was added dropwise    into the reaction mixture. The mixture was warmed to room    temperature and stirred overnight. The reaction was then quenched    with water and extracted with ethyl acetate. The organics were    washed with brine, dried over anhydrous sodium sulfate and    concentrated in vacuo. The residue was crystallized from    ether/hexane to give the title compound (8.93 g, 80%) as a white    solid.-   B.    4-Benzyloxy-3-[2-(2,3-dihydrobenzofuran-5-yl)-vinyl]indole-1-carboxylic    acid diethylamide: To a solution of    [(2,3-dihydro-benzofuran-5-yl)methyl]triphenylphosphonium bromide    (10 g, 21.05 mmol) (prepared according to: Harrowven, D. C. et al in    Tetrahedron, 2001, 57, 4447–4454) in THF (200 mL) at −78° C. was    added LDA (10.6 mL, 21.05 mmol) and the resulting reaction mixture    was allowed to stir at −78° C. for 1 h. Thereafter, the aldehyde    prepared in the previous step (2.5 g, 7.14 mmol) was added and the    resulting reaction mixture was allowed to stir at room temperature    for 2 h. The reaction mixture was poured onto 0.2 M HCl and    extracted with ethyl acetate. The combined ethyl acetate extracts    were washed with brine, dried over anhydrous sodium sulfate and    concentrated in vacuo. Chromatography (SiO₂, 0–25% Ethyl    Acetate-Hexanes eluant) provided the desired compound in    quantitative yield.-   C.    3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-4-hydroxy-indole-1-carboxylic    acid diethylamide: To a solution of the vinyl urea prepared in step    B (400 mg, 0.86 mmol) in EtOAc (10 mL) and EtOH (10 mL) at room    temperature was added 10% Pd/C (80 mg) and the resulting reaction    mixture was allowed stir in a Parr Shaker under 10 psi hydrogen    pressure for 5 h. The reaction mixture upon removal from the Parr    Shaker was filtered through a pad of Celite and the filterate    concentrated in vacuo. Chromatography (SiO₂, 0–25% Ethyl    Acetate-Hexanes eluant) provided 1.1 g of the desired compound (1.62    g theoretical, 68% yield).-   D.    2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside:    To a solution of the urea prepared in step C (1 g, 2.65 mmol) in    acetone (8 mL) at room temperature was added potassium carbonate    (1.82 g, 13.2 mmol) followed by    2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (1.17 g, 5.27    mmol) and the resulting reaction mixture was allowed to stir at room    temperature for 72 h. The reaction mixture was filtered through    Celite and the filtrate washed with ethyl acetate. The combined    organic layers were concentrated in vacuo. Chromatography (SiO₂,    0–20% Ethyl Acetate-Hexanes eluant) provided 0.54 g of the desired    compound (1.87 g theoretical, 29% yield).-   E.    2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}β-D-glucopyranoside:    To a solution of the acetyl indole prepared in step D (530 mg, 0.75    mmol) in ethanol (50 mL) was added 25% NaOH (16 mL) and the    resulting reaction mixture was allowed to stir at reflux for 3 h.    The reaction mixture was diluted with water (200 mL) and the pH    adjusted to 11 with the addition of 1 N HCl. The reaction mixture    was then concentrated in vacuo to remove ethanol. The aqueous layer    was extracted with ethyl acetate. The combined ethyl acetate    extracts were washed with brine, dried over anhydrous magnesium    sulfate and concentrated in vacuo. Chromatography (SiO₂, 0–10%    MeOH—CH₂Cl₂ eluant) provided 290 mg of the desired compound as a    white solid (330 mg theoretical yield, 88% yield). ¹HNMR (300 MHz,    CD₃OD) δ 7.1(s, 1H), 7–6.85(m, 3H), 6.77(s, 1H), 6.75–6.65(m, 1H),    6.58(d, J=8 Hz, 1H), 5.2(d, J=8 Hz, 1H), 4.47(t, J=8 Hz, 2H),    3.95–3.85(m, 1H), 3.75–3.7(m, 1H), 3.6–3.55(m, 1H), 3.5–3.4(m, 3H),    3.15 (t, J=8 Hz, 2H), 3.1–2.9(m, 4H), 2.9–2.8(m, 1H). MS: m/z (MH⁺)    442.

EXAMPLE 22-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-6-O-acetylβ-D-glucopyranoside

The title compound was isolated as a by-product in Example 1, Part E.¹HNMR (300 MHz, CD₃OD) δ 7.1–7.05(m, 1H), 7.0–6.9(m, 3H), 6.76(s, 1H),6.7–6.65(m, 1H), 6.58(d, J=8 Hz, 1H), 5.17(d, J=7 Hz, 1H), 4.46(t, J=8Hz, 2H), 4.45–4.35(m, 1H), 4.25–4.2(m, 1H), 3.7–3.6(m, 2H), 3.55–3.4(m,2H), 3.3–3.2(m, 1H), 3.14(t, J=8 Hz, 2H), 3.1–2.8(m, 3H), 1.92(s, 3H).MS: m/z (MH⁺) 484.

EXAMPLE 32-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1-methyl-1H-indol-4-yloxy}β-D-glucopyranoside

-   A. 4-Benzyloxy-1-methyl-1H-indole-3-carbaldehyde: To a solution of    commercially available 4-benzyloxy-1H-indole-3-carbaldehyde (1 g,    3.98 mmol) in DMF (15 mL) at 0° C. was added NaH (262 mg, 8.75 mmol,    80% dispersion in oil) followed by methyl iodide (0.25 mL, 3.98    mmol) and the resulting reaction mixture was allowed to stir at room    temperature for 6 h. The reaction mixture was poured onto water and    extracted with ethyl acetate. The combined ethyl acetate extracts    were washed with brine, dried over anhydrous sodium sulfate and    concentrated in vacuo to provide the desired compound in    quantitative yield.-   B.    2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1-methyl-1H-indol-4-yloxy}β-D-glucopyranoside:    The title compound was prepared from    4-benzyloxy-1-methyl-1H-indole-3-carbaldehyde (preparation described    in Part A) and    [(2,3-dihydro-benzofuran-5-yl)methyl]triphenylphosphonium bromide by    the same procedure as described in step B through E in Example 1.    ¹HNMR (300 MHz, CDCl₃) δ 7.1–7.0(m, 1H), 6.95–6.8(m, 3H), 6.7–6.6(m,    1H), 6.55–6.5(m, 1H), 4.95(d, J=8 Hz, 2H), 4.3–4.3(m, 1H),    4.0–3.9(m, 1H), 3.8–3.65(m, 2H), 3.6(s, 3H), 3.6–5(m, 2H),    3.45–3.4(m, 1H), 3.15–3.0(m, 3H), 2.95–2.85(m, 2H), 2.65–2.55(m,    1H). MS: m/z (MH⁺) 456.

EXAMPLE 4 2-[3-(2-Benzo[1,3]dioxol-5-yl-ethyl)-1H-indol-4-yloxy]β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide prepared instep A of Example 1 and 5-piperonylmethyl triphenylphosphonium bromideby the same procedure as described in Example 1. ¹HNMR (300 MHz,CD₃COCD₃) δ 9.88 (br s, 1H), 7.05–6.9 (m, 3H), 6.8 (s, 1H), 6.75–6.65(m, 3H), 5.9 (s, 2H), 5.2 (d, J=7 Hz, 1H), 4.4(br s, 2H), 3.95–3.85(m,1H), 3.8–3.5(m, 6H), 3.3–3.2(m, 1H), 3.15–2.85(m, 6H). MS: m/z (MH⁺)444.

EXAMPLE 52-{3-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and2,3-dihydro-benzo[1,4]dioxo-6-meyl triphenylphosphonium bromide by thesame procedure as described in Example 1. ¹HNMR (300 MHz, CD₃COCD₃) δ9.89 (br s, 1H), 7.05–6.95(m, 3H), 6.8–6.65(m, 4H), 5.2(d, J=7 Hz, 1H),4.4–4.25(m, 2H), 4.2 (s, 4H), 3.95–3.85(m, 1H), 3.75–3.55(m, 6H),3.3–3.2(m, 1H), 3.15–2.8(m, 5H). MS: m/z (M⁺) 457.

EXAMPLE 62-[3-(2-Naphthalen-2-yl-ethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and2-naphthylmethyltriphenylphosphonium chloride by the same procedure asdescribed in Example 1. ¹HNMR (300 MHz, CD₃COCD₃) δ 9.89(br s, 1H),7.9–7.75(m, 4H), 7,55–7.35(m, 3H), 7.1–6.9(m, 3H), 6.74(d, J=7 Hz, 1H),5.26(d, J=7 Hz, 1H), 4.5–4.4(m, 2H), 3.95–3.85(m, 1H), 3.8–3.55(m, 6H),3.45–3.35(m, 1H), 3.25–3.1(m, 5H). MS: m/z (M⁺+Na) 472.

EXAMPLE 72-{3-[2-(4-Methoxy-phenyl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and4-methoxybenzyl triphenyphosphonium chloride by the same procedure asdescribed in Example 1. ¹HNMR (300 MHz, CD₃COCD₃) δ 9.87 (br s, 1H),7.20 (d, J=7 Hz, 2H), 7.05–6.9(m, 3H), 6.8(d, J=8 Hz, 2H), 6.7(d, J=7Hz, 1H), 5.2(d, J=7 Hz, 1H), 4.5–4.3(m, 2H), 3.95–3.85(m, 1H), 3.75(s,3H), 3.7–3.5(m, 6H), 3.3–3.2(m, 1H), 3.15–2.85(m, 5H). MS: m/z (M⁺) 429.

EXAMPLE 82-{3-[2-(4-Ethoxy-phenyl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and4-ethoxybenzyl triphenyphosphonium chloride by the same procedure asdescribed in Example 1. ¹HNMR (300 MHz, CD₃COCD₃) δ 9.8(br s, 1H),7.2(d, J=8 Hz, 2H), 7.05–6.95(m, 3H), 6.8(d, J=8 Hz, 2H), 6.7(d, J=7 Hz,1H), 5.22 (d, J=7 Hz, 1H), 4.0(q, J=7 Hz, 2H), 3.95–3.85(m, 1H),3.75–3.5(m, 6H), 3.35–3.25(m, 1H), 3.15–2.9(m, 5H), 1.35(t, J=7 Hz, 3H).MS: m/z (M⁺+Na) 466.

EXAMPLE 92-{3-[2-(4-Ethyl-phenyl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and(4-ethylbenzyl)triphenylphosphonium chloride by the same procedure asdescribed in Example 1. ¹HNMR (300 MHz, CD₃COCD₃) δ 9.8(br s, 1H),7.2(d, J=8 Hz, 2H), 7.1(d, J=8 Hz, 2H), 7.05–6.8(m, 3H), 6.7(d, J=7 Hz,1H), 5.2(d, J=7 Hz, 1H), 4.5–4.3(m, 2H), 3.95–3.85(m, 1H), 3.8–3.5(m,6H), 3.35–3.25(m, 1H), 3.15–2.9(m, 5H), 2.6(q, J=7 Hz, 2H), 1.2(t, J=7Hz, 3H). MS: m/z (MH⁺) 428.

EXAMPLE 102-{3-[2-(4-Methoxy-phenyl)-ethyl]-6-methyl-1H-indol-4-yloxy}-β-D-glucopyranoside

-   A. 2-Benzyloxy-4-methylbenzaldehyde: To a solution of commercially    available 2-hydroxy-4-methylbenzaldehyde (20 g, 147.05 mmol) in DMF    (200 mL) at 0° C. was added sodium hydride (6.47 g, 161.76 mmol, 60%    oil dispersion) followed by the dropwise addition of benzyl bromide    (19.3 mL, 161.76 mmol). Upon completion of addition of benzyl    bromide, the ice bath is removed and the reaction mixture was    stirred at room temperature for 4 h. The reaction mixture was poured    onto water and extracted with ethyl acetate. The combined ethyl    acetate extracts were dried over anhydrous sodium sulfate and    concentrated in vacuo. Chromatography (SiO₂, 2–5% EtOAc-Hexanes    eluant) provided 29.58 g of the desired product as a white solid    (33.24 g theoretical, 89% yield).-   B. 2-Azido-3-(2-benzyloxy-4-methyphenyl)-acrylic acid ethyl ester:    To a solution of sodium ethoxide (46 mL, 3.1 M in ethanol) in    ethanol (50 mL) at −15° C. was added dropwise a solution of the    aldehyde prepared in the previous step (4 g, 17.7 mmol) and ethyl    azidoacetate (23 mL, 53.09 mmol, 2.3 M solution in dichloromethane)    and the resulting reaction mixture was allowed to stir at 15° C. for    72 h. The reaction mixture was poured onto saturated sodium    bicarbonate and the extracted with ethyl acetate. The combined ethyl    acetate extracts were dried over anhydrous sodium sulfate and    concentrated in vacuo. The crude product (4.15 g) was used as is    without further purification in the next step of the synthetic    sequence.-   C. 4-Benzyloxy-6-methyl-1H-indole-2-carboxylic acid ethyl ester: A    solution of the azido compound prepared in the previous step    (4.15 g) in toluene (60 mL) was refluxed for 18 h. The reaction    mixture was concentrated in vacuo. Chromatography (SiO₂, 5–10%    EtOAC-Hexanes eluant) provided 2.52 g of the desired product as a    yellow solid (5.47 g, 46% yield over two steps).-   D. 4-Benzyloxy-6-methyl-1H-indole-2-carboxylic acid: To a solution    of the ester prepared in the previous step (500 mg, 1.62 mmol) in    tetrahydrofuran (4 mL) at room temperature was added lithium    hydroxide (240 mg, 10 mmol) followed by water (2 mL) and methanol (2    mL) and the resulting reaction mixture was allowed to stir at room    temperature for 72 h. The reaction mixture was poured onto 15%    citric acid and extracted with ethyl acetate. The combined ethyl    acetate extracts were dried over anhydrous sodium sulfate and    concentrated in vacuo to provide 437 mg of the desired product as an    off white solid (455 mg theoretical, 96% yield).-   E. 4-Benzyloxy-6-methyl-1H-indole: To a solution of the acid    prepared in the previous step (150 mg, 0.53 mmol) in quinoline (2    mL) at room temperature was added copper powder (10 mg, 0.16 mmol)    and the resulting reaction mixture was allowed to stir at 235° C.    for 900 seconds in a microwave reactor. The reaction mixture was    poured onto 1 N HCl and extracted with ethyl acetate. The combined    ethyl acetate extracts were dried over anhydrous sodium sulfate and    concentrated In vacuo. Chromatography (SiO₂, 10 to 20% Ethyl    Acetate-Hexanes eluant) provided 617 mg of the desired product as a    dark oil (759 mg theoretical, 81% yield).-   F. 4-Benzyloxy-6-methyl-1H-indole-3-carbaldehyde: To a solution of    POCl₃ (1 mL) in DMF (4 mL) at 0° C. was added indole prepared in the    previous step (617 mg, 02.59 mmol) in THF (6 mL) and the resulting    reaction mixture was allowed to stir with warming to room    temperature for 3 h. The reaction mixture was poured on to saturated    sodium bicarbonate and extracted with ethyl acetate. The combined    ethyl acetate extracts were dried over anhydrous sodium sulfate and    concentrated in vacuo. Chromatography (SiO₂, 40% Ethyl    Acetate-Hexanes eluant) provided 220 mg of the desired compound as a    pale yellow solid (686 mg theoretical, 32% yield).-   G. 4-Benzyloxy-3-formyl-6-methyl-indole-1-carboxylic acid    diethylamide: To a solution of aldehyde prepared in the previous    step (240 mg, 0.91 mmol) in tetrahydrofuran (6 mL) at room    temperature was added sodium hydride (54 mg, 1.35 mmol, 60%    dispersion in oil) and the resulting reaction mixture was allowed to    sitr at room temperature for 0.5 h. Thereafter N,N-diethylcarbamyl    chloride (0.17 mL, 1.35 mmol) was added and the reaction mixture was    allowed to stir at room temperature for 18 h. The reaction mixture    was poured onto water and extracted with ethyl acetate. The combined    ethyl extracts were dried over anhydrous sodium sulfate and    concentrated in vacuo. Chromatography (SiO₂, 30% EtOAc-Hexanes    eluant) provided 290 mg of the desired product as a pale yellow    solid (331 mg theoretical, 88% yield).-   H.    2-{3-[2-(4-Methoxy-phenyl)-ethyl]-6-methyl-1H-indol-4-yloxy}-β-D-glucopyranoside:    The title compound was prepared from    4-benzyloxy-3-formyl-6-methyl-indole-1-carboxylic acid diethylamide    and 4-methoxybenzyl triphenyphosphonium chloride by the same    procedure as described in Example 1. ¹HNMR (300 MHz, CD₃COCD₃) δ 9.7    (br s, 1H), 7.19(d, J=8 Hz, 2H), 6.9–6.75(m, 4H), 6.56(s, 1H),    5.21(d, J=7 Hz, 1H), 4.4–4.25(m, 2H), 3.95–3.85(m, 1H), 3.75(s, 3H),    3.7–3.5(m, 5H), 3.3–3.2(m, 1H), 3.15–2.8(m, 4H), 2.8(s, 3H). MS: m/z    (MH⁺) 444.

EXAMPLE 11 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

-   A. 4-Benzyloxy-3-(4-ethyl-benzyl)-indole-1-carboxylic acid    diethylamide: To a solution of    4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared    in step A of Example 1 (1.0 g, 2.8 mmol) in 6 mL of anhydrous THF    was added dropwise a 0.5 M solution of 4-ethylphenylmagnesium    bromide in anhydrous THF (6.2 mL, 3.1 mmol) at 0° C. The reaction    mixture was continued stirring at 0° C. for 30 min, quenched with    saturated ammonium chloride solution and extracted with ethyl    acetate. The organic extracts were dried over sodium sulfate and    concentrated in vacuo. The crude product was used directly in the    next step. To a solution of the crude indolecarbinol in 6 mL    dichloromethane was added triethylsilane (0.46 g, 4.0 mmol) at −78°    C., followed by addition of a 1.0 M solution of stannic chloride in    dichloromethane (3.6 mL, 3.6 mmol). The reaction mixture was    continued stirring at −78° C. for 20 min, quenched with water and    warmed to room temperature. After extraction with dichloromethane,    the organic extracts were dried over sodium sulfate, concentrated in    vacuo and chromatographed with silica gel eluting with ethyl    acetate/hexane (25:100) to provide the title compound (0.91 g,    yield: 74%) as colorless oil.-   B. 3-(4-Ethyl-benzyl)-4-hydroxy-indole-1-carboxylic acid    diethylamide: A solution of Part A (0.91 g, 2.1 mmol) in ethanol (10    mL) and ethyl acetate (20 mL) was hydrogenated over 10% Pd—C    (0.18 g) under H₂ (14 psi) for 7 h. The catalyst was removed by    filtration and the filtrate was concentrated in vacuo. The crude    product was purified by chromatography on silica gel eluting with    methanol/chloroform (4:100) to provide the title compound (0.42 g,    57%) as a white solid.-   C.    [1-Diethylcarbamoyl-3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-2,3,4,6-tetra-O-acetyl-]-β-D-glucopyranoside:    To a solution of Part B (0.42 g, 1.2 mmol) in acetone (2.4 mL) was    added potassium carbonate (0.79 g, 6 mmol), followed by addition of    2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (1.08 g, 2.6    mmol). The reaction mixture was stirred at room temperature for    24 h. Then solids were filtered and washed with ethyl acetate. The    organic extracts were washed with water and brine, dried over    anhydrous sodium sulfate and concentrated in vacuo. The crude    product was purified by chromatography on silica gel eluting with    ethyl acetate/hexane (50:50) to provide the title compound (0.37 g,    45%).-   D. 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside: Part    C (0.37 g, 0.5 mmol) was dissolved in ethanol (30 mL) and 25%    aqueous sodium hydroxide (10 mL) and the resulting solution was    brought to reflux for 3 h. After cooling to room temperature, the    mixture was diluted with water (20 mL), concentrated in vacuo to    remove most of ethanol, and extracted with ethyl acetate. The    organic extracts were washed with water and brine, dried over    anhydrous sodium sulfate and concentrated in vacuo. The crude    product was purified by chromatography on silica gel eluting with    methanol/chloroform (10:100) to provide the final product (0.16 g,    76%) as an off-white solid. ¹HNMR (300 MHz, CD₃OD) δ 7.18 (d, J=8.0    Hz, 2H), 7.07 (d, J=7.86 Hz, 2H), 7.01–6.97 (m, 2H), 6.68 (s, 1H),    6.66 (d, J=2.21 Hz, 1H), 5.08 (d, J=7.39 Hz, 1H), 4.34 (d, J=16.2    Hz, 1H), 4.25 (d, J=15.9 Hz, 1H), 3.88 (dd, J=2.03, 11.93 Hz, 1H),    3.68 (dd, J=5.42, 12.2 Hz, 1H), 3.50–3.41 (m, 4H), 2.59 (q, J=7.41    Hz, 2H), 1.21 (t, J=7.54 Hz, 3H). MS: m/z (MH⁺) 414.

EXAMPLE 122-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-methoxycarbonyl-β-D-glucopyranoside

A 1.0 M solution of methyl chloroformate in dichloromethane (0.24 mL,0.24 mmol) was added dropwise to a solution of2-[3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside (Example 11,0.093 g, 0.22 mmol) in 2,4,6-collidine (1 mL) at −30° C. The mixture waswarmed to room temperature over the period of 2 h, and stirred at roomtemperature overnight. The reaction was quenched with the addition ofwater and the mixture was diluted with diethyl ether. The pH of theaqueous layer was adjusted to pH 7 by addition of cold 1N HCl, and themixture was extracted with diethyl ether. The organics were washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The crude product was purified by chromatography on silica gel elutingwith methanol/chloroform (8:100) to provide the final product (0.052 g,50%) as an off-white solid. ¹HNMR (300 MHz, CD₃OD) δ 7.18 (d, J=8.15 Hz,2H), 7.08 (d, J=8.05 Hz, 2H), 7.02–6.93 (m, 2H), 6.64–6.61 (m, 2H), 5.04(d, J=7.35 Hz, 1H), 4.44 (dd, J=2.21, 11.7 Hz, 1H), 4.35–4.27 (m, 3H),3.70 (s, 3H), 3.66–3.61 (m, 1H), 3.49–3.40 (m, 2H), 3.38–3.36 (m, 1H),2.59 (q, J=7.76 Hz, 2H), 1.21 (t, J=7.66 Hz, 3H). MS: m/z (MH⁺) 472.

EXAMPLE 132-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-β-D-glucopyranoside

The title compound was prepared from2-[3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside (Example 11)and ethyl chloroformate by the same procedure as described in Example12. ¹HNMR (300 MHz, CD₃OD) δ 7.18 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.0 Hz,2H), 7.01–6.93 (m, 2H), 6.64 (s, 1H), 6.62 (s, 1H), 5.04 (d, J=7.32 Hz,1H), 4.43 (dd, J=2.1, 11.7 Hz, 1H), 4.32–4.27 (m, 3H), 4.14–4.06 (m,2H), 3.66–3.61 (m, 1H), 3.49–3.42 (m, 2H), 3.40–3.36 (m, 1H), 2.59 (q,J=7.76 Hz, 2H), 1.26–1.18 (m, 6H). MS: m/z (MH⁺) 486.

EXAMPLE 142-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-hexanoyl-β-D-glucopyranoside

A solution of hexanoyl chloride (0.072 mg, 0.53 mmol) in dichloromethane(0.05 mL) was added dropwise to a solution of²-[3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside (Example 11,0.22 g, 0.53 mmol) in 2,4,6-collidine (2 mL) at −30° C. The mixture wasstirred below 0° C. for 30 min. The reaction was quenched with theaddition of water and the mixture was diluted with diethyl ether. The pHof the aqueous layer was adjusted to pH 7 by addition of cold 1N HCl,and the mixture was extracted with diethyl ether. The organics werewashed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo. The crude product was purified by chromatography on silica geleluting with methanol/chloroform (8:100) to provide the final product(0.207 g, 76%) as an off-white solid. ¹HNMR (300 MHz, CD₃OD) δ 7.17 (d,J=8.06 Hz, 2H), 7.07 (d, J=8.12 Hz, 2H), 7.02–6.93 (m, 2H), 6.64–6.61(m, 2H), 5.03 (d, J=7.31 Hz, 1H), 4.41–4.38 (m, 1H), 4.29–4.20 (m, 3H),3.65–3.59 (m, 1H), 3.49–3.43 (m, 2H), 3.38–3.36 (m, 1H), 2.59 (q, J=7.42Hz, 2H), 2.28 (t, J=7.22 Hz, 2H), 1.57–1.52 (m, 2H), 1.27–1.18 (m, 7H),0.85 (t, J=6.85 Hz, 3H). MS: m/z (MH⁺) 512.

EXAMPLE 15 2-[3-(4-Methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and4-methylphenylmagnesium bromide by the same procedure as described inExample 11. ¹HNMR (300 MHz, CD₃OD) δ 7.15 (d, J=7.86 Hz, 2H), 7.04 (d,J=7.9 Hz, 2H), 6.99–6.96 (m, 2H), 6.68–6.65 (m, 2H), 5.07 (d, J=7.22 Hz,1H), 4.32 (d, J=16.1 Hz, 1H), 4.24 (d, J=16.0 Hz, 1H), 3.87 (dd, J=1.79,11.89 Hz, 1H), 3.68 (dd, J=5.44, 12.1 Hz, 1H), 3.48–3.35 (m, 4H), 2.28(s, 3H). MS: m/z (MH⁺) 400.

EXAMPLE 162-[3-(3-Fluoro-4-methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and3-fluoro-4-methylphenylmagnesium bromide by the same procedure asdescribed in Example 11. ¹HNMR (300 MHz, CD₃COCD₃) δ 10.01 (br s, 1H),7.1–6.9(m, 5H), 6.85–6.8(m, 1H), 6.7(d, J=7 Hz, 1H), 5.2(d, J=7 Hz, 1H),4.6–4.55(m, 1H), 4.3(dd, J=15 Hz, 51 Hz, 2H), 3.95–3.85(m, 1H),3.8–3.7(m, 1H), 3.6–3.5(m, 4H). MS: m/z (M⁺+Na) 440.

EXAMPLE 17 2-[3-(4-propyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and4-propylphenylmagnesium bromide by the same procedure as described inExample 11. ¹HNMR (300 MHz, CD₃OD) δ 7.17 (d, J=7.91 Hz, 2H), 7.05 (d,J=7.86 Hz, 2H), 7.00–6.94 (m, 2H), 6.68–6.65 (m, 2H), 5.08 (d, J=6.94Hz, 1H), 4.34 (d, J=16.1 Hz, 1H), 4.25 (d, J=16.0 Hz, 1H), 3.88 (dd,J=1.83, 12.2 Hz, 1H), 3.68 (dd, J=5.43, 12.1 Hz, 1H), 3.49–3.39 (m, 4H),2.54 (t, J=7.49 Hz, 2H), 1.66–1.58 (m, 2H), 0.93 (t, J=7.31 Hz, 3H). MS:m/z (MH⁺) 428.

EXAMPLE 182-[3-(4-isopropyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and4-isopropylphenylmagnesium bromide by the same procedure as described inExample 11. ¹HNMR (300 MHz, CD₃OD) δ 7.19 (d, J=8.07 Hz, 2H), 7.10 (d,J=8.06 Hz, 2H), 7.01–6.94 (m, 2H), 6.68–6.65 (m, 2H), 5.09 (d, J=7.03Hz, 1H), 4.34 (d, J=15.9 Hz, 1H), 4.24 (d, J=16.0 Hz, 1H), 3.88 (dd,J=1.74, 11.8 Hz, 1H), 3.67 (dd, J=5.42, 12.2 Hz, 1H), 3.49–3.37 (m, 4H),2.89–2.80 (m, 1H), 1.22 (d, J=7.0 Hz, 6H). MS: m/z (MH⁺) 428.

EXAMPLE 192-(3-Biphenyl-4-ylmethyl-1H-indol-4-yloxy)-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and4-biphenylmagnesium bromide by the same procedure as described inExample 11. ¹HNMR (300 MHz, CD₃OD) δ 7.58 (d, J=8.08 Hz, 2H), 7.50 (d,J=8.11 Hz, 2H), 7.41–7.35 (m, 4H), 7.28 (t, J=7.47 Hz, 1H), 7.02–6.69(m, 2H), 6.77 (s, 1H), 6.68 (d, J=5.12 Hz, 1H), 5.10 (d, J=7.49 Hz, 1H),4.44 (d, J=15.9 Hz, 1H), 4.31 (d, J=15.9 Hz, 1H), 3.88 (dd, J=2.09, 12.1Hz, 1H), 3.66 (dd, J=5.62,12.0 Hz, 1H), 3.51–3.36 (m, 4H). MS: m/z (MH⁺)462.

EXAMPLE 202-[3-(2-Fluoro-biphenyl-4-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and3-fluoro-4-biphenylmagnesium bromide by the same procedure as describedin Example 11. ¹HNMR (300 MHz, CD₃OD) δ 7.53–7.50 (m, 2H), 7.43–7.31 (m,4H), 7.21 (d, J=1.46 Hz, 1H), 7.18–7.00 (m, 3H), 6.87 (s, 1H), 6.71 (dd,J=2.06, 6.62 Hz, 1H), 5.11 (d, J=7.17 Hz, 1H), 4.49 (d, J=15.8 Hz, 1H),4.29 (d, J=15.9 Hz, 1H), 3.88 (dd, J=2.23, 12.1 Hz, 1H), 3.66 (dd,J=5.66, 12.0 Hz, 1H), 3.52–3.42 (m, 3H), 3.39–3.35 (m, 1H). MS: m/z(MH⁺) 480.

EXAMPLE 212-[1-Diethylcarbamoyl-3-(4-methoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

[1-Diethylcarbamoyl-3-(4-methoxy-benzyl)-1H-indol-4-yloxy]-2,3,4,6-tetra-O-acetyl-]-β-D-glucopyranoside(0.13 g, 0.19 mmol, prepared from 4-benzyloxy-N,N-diethylcarbamyl indole3-carboxaldehyde, prepared in step A of Example 1, and4-methoxyphenyl-magnesium bromide by the same procedure as described inExample 11, Part A, B and C) was dissolved in methanol (1 mL) and (0.2mL), followed by addition of excess of potassium carbonate. Theresulting mixture was stirred at room temperature overnight. Tent solidswere filtered and washed with ethyl acetate. The ethyl acetate solutionwas washed with water and brine, dried over anhydrous sodium sulfate andconcentraded in vacuo. The product was purified by chromatography onsilica gel, eluting with methanol/chloroform (10:100), to give the titlecompound (0.03 g, yield: 31%) as a white solid. ¹HNMR (300 MHz, CD₃OD) δ7.26–7.20 (m, 4H), 6.92–6.86 (m, 3H), 6.68 (s, 1H), 5.12 (d, J=7.11 Hz,1H), 4.30–428 (m, 2H), 3.90–3.80 (m, 1H), 3.79 (s, 3H), 3.77–3.65 (m,2H), 3.64–3.51 (m, 2H), 3.50–3.40 (m, 5H), 1.22–1.15 (m, 6H). MS: m/z(MH⁺) 515.

EXAMPLE 22 2-[3-(4-Methoxy-benzil)-1H-indol-4-yloxy]-β-D-glucopyranoside

[1-Diethylcarbamoyl-3-(4-methoxy-benzyl)-1H-indol-4-yloxy]-2,3,4,6-tetra-O-acetyl-]-β-D-glucopyranoside(0.16 g, 0.23 mmol, prepared from 4-benzyloxy-N,N-diethylcarbamyl indole3-carboxaldehyde prepared in step A of Example 1, and4-methoxyphenyl-magnesium bromide by the same procedure as described inExample 11, Part A, B and C) was dissolved in ethanol (15 mL) and 25%aqueous sodium hydroxide (5 mL) and the resulting solution was broughtto reflux for 3 h. After cooling to room temperature, the mixture wasdiluted with water (20 mL), concentrated in vacuo to remove most ofethanol, and extracted with ethyl acetate. The organic extracts werewashed with water and brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel eluting with methanol/chloroform (10:100) to provide thefinal product (0.062 g, 65%) as an off-white solid. ¹HNMR (300 MHz,CD₃OD) δ 7.18 (d, J=8.59 Hz, 2H), 6.98–6.96 (m, 2H), 6.81–6.78 (m, 2H),6.68–6.65 (m, 2H), 5.08 (d, J=7.25 Hz, 1H), 4.30 (d, J=16.1 Hz, 1H),4.21 (d, J=16.1 Hz, 1H), 3.88 (dd, J=1.98, 12.2 Hz, 1H), 3.75 (s, 3H),3.71–3.57 (m, 2H), 3.49–3.40 (m, 3H). MS: m/z (MH⁺) 416.

EXAMPLE 232-[3-(4-Methoxy-benzyl)-1-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside

-   A. 4-Benzyloxy-3-(4-methoxy-benzyl)-1H-indole:    4-Benzyloxy-3-(4-methoxy-benzyl)-indole-1-carboxylic acid    diethylamide (0.38 g, 0.86 mmol, prepared from    4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared    in step A of Example 1, and 4-methoxyphenyl-magnesium bromide by the    same procedure as described in Example 11, Part A) was dissolved in    ethanol (15 mL) and 25% aqueous sodium hydroxide (5 mL) and the    resulting solution was brought to reflux for 3 h. After cooling to    room temperature, the mixture was diluted with water (20 mL),    concentrated in vacuo to remove most of ethanol, and extracted with    ethyl acetate. The organic extracts were washed with water and    brine, dried over anhydrous sodium sulfate and concentrated in    vacuo. The crude product (0.25 g, 86%, a yellow solid) was pure and    used directly in the next step.-   B. 4-Benzyloxy-3-(4-methoxy-benzyl)-1-methyl-1H-indole: To a    suspension of sodium hydride (0.029 g, 38 mmol, 60% in oil    suspension) in anhydrous DMF (0.5 mL) was added dropwise a solution    of Part A (0.24 g, 0.69 mmol) in anhydrous DMF (2 mL) at 0° C. After    stirring at 0° C. for 15 min, iodomethane (0.11 g, 0.76 mmol) was    added dropwise into the reaction mixture. The mixture was warmed to    room temperature and stirred for 30 min. The reaction was then    quenched with water and extracted with ethyl acetate. The organics    were washed with brine, dried over anhydrous sodium sulfate and    concentrated in vacuo. The crude product (0.24 g, 99%, an orange    oil) was pure and used directly in the next step.-   C. 3-(4-Methoxy-benzyl)-1-methyl-1H-indol-4-ol: A solution of Part B    (0.24 g, 0.69 mmol) in ethanol (5 mL) and ethyl acetate (10 mL) was    hydrogenated over 10% Pd—C (0.05 g) under H₂ (50 psi) for 3 h. The    catalyst was removed by filtration and the filtrate was concentrated    in vacuo. The crude product was purified by chromatography on silica    gel eluting with methanol/chloroform (4:100) to provide the title    compound (0.17 g, 92%) as a yellow solid.-   D.    2-[3-(4-methoxy-benzyl)-1-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside:    To a solution of Part C (0.17 g, 0.63 mmol) in acetone (1 mL) was    added potassium carbonate (0.43 g, 3.2 mmol), followed by addition    of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.51 g, 1.2    mmol). The reaction mixture was stirred at room temperature for    24 h. Then solids were filtered and washed with ethyl acetate. The    ethyl acetate solution was washed with water and brine, dried over    anhydrous sodium sulfate and concentrated in vacuo. The residue was    dissolved in methanol (2 mL) and chloroform (0.5 mL), followed by    addition of excess of potassium carbonate. The resulting mixture was    stirred at room temperature for 4 h. Then solids were filtered and    washed with ethyl acetate. The ethyl acetate solution was washed    with water and brine, dried over anhydrous sodium sulfate and    concentrated in vacuo. The product was purified by chromatography on    silica gel eluting with methanol/chloroform (10:100) to give the    final product (0.035 g, yield: 9%) as a white solid. ¹HNMR (300 MHz,    CD₃OD) δ 7.18 (d, J=8.68 Hz, 2H), 7.07–7.02 (m, 1H), 6.96 (d, J=7.62    Hz, 1H), 6.82–6.79 (d, J=8.6 Hz, 2H), 6.71 (d, J=7.24 Hz, 1H), 6.59    (s, 1H), 5.08 (d, J=7.04 Hz, 1H), 4.30 (d, J=16.0 Hz, 1H), 4.20 (d,    J=16.0 Hz, 1H), 3.88 (dd, J=1.79, 12.0 Hz, 1H), 3.75 (s, 3H),    3.71–3.65 (m, 4H), 3.50–3.40 (m, 4H). MS: m/z (MH⁺) 430.

EXAMPLE 242-[3-(3-Fluoro-4-methoxy-benzyl)-1H-indol-4-yloxy]-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared instep A of Example 1, and 3-fluoro-4-methoxyphenylmagnesium bromide bythe same procedure as described in Example 11. ¹HNMR (300 MHz, CD₃OD) δ7.03–6.91 (m, 5H), 6.75 (s, 1H), 6.70–6.67 (m, 1H), 5.08 (d, J=7.46 Hz,1H), 4.34 (d, J=15.9 Hz, 1H), 4.17 (d, J=16.1 Hz, 1H), 3.87 (dd, J=2.17,12.1 Hz, 1H), 3.82 (s, 3H), 3.66 (dd, J=5.61, 12.0 Hz, 1H), 3.48–3.34(m, 4H). MS: m/z (MH⁺) 434.

EXAMPLE 25 2-[3-(4-Ethoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared instep A of Example 1, and 4-ethoxyphenylmagnesium bromide by the sameprocedure as described in Example 11. ¹HNMR (300 MHz, CD₃OD) δ 7.17 (d,J=8.68 Hz, 2H), 6.99–6.96 (m, 2H), 6.81–6.78 (m, 2H), 6.68 (s, 2H), 6.66(d, J=2.33 Hz, 2H), 5.09 (d, J=7.34 Hz, 1H), 4.31 (d, J=16.0 Hz, 1H),4.22 (d, J=15.9 Hz, 1H), 3.99 (q, J=7.01 Hz, 2H), 3.88 (dd, J=1.86,11.98 Hz, 1H), 3.68 (dd, J=5.26, 12.0 Hz, 1H), 3.50–3.40 (m, 4H), 1.36(t, J=7.06 Hz, 3H). MS: m/z (MH⁺) 430.

EXAMPLE 26 2-[3-(4-Phenoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared instep A of Example 1, and 4-phenoxyphenylmagnesium bromide by the sameprocedure as described in Example 11. ¹HNMR (300 MHz, CD₃OD) δ 7.32–7.25(m, 4H), 7.06–6.93 (m, 5H), 6.87 (d, J=8.68 Hz, 3H), 6.76 (s, 1H), 6.68(dd, J=2.13, 6.04 Hz, 1H), 5.09 (d, J=6.97 Hz, 1H), 4.39 (d, J=15.6 Hz,1H), 4.25 (d, J=16.2 Hz, 1H), 3.89 (d, J=11.8 Hz, 1H), 3.67 (dd, J=5.50,12.0 Hz, 1H), 3.50–3.37 (m, 4H). MS: m/z (MH⁺) 478.

EXAMPLE 272-[3-(4-Methylsulfanyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

-   A. 4-Hydroxy-3-(4-methylsulfanyl-benzyl)-indole-1-carboxylic acid    diethylamide: To a solution of    4-benzyloxy-3-(4-methylsulfanyl-benzyl)-indole-1-carboxylic acid    diethylamide (0.63 g, 1.38 mmol, prepared from    4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide and    4-methylsulfanyl-phenylmagnesium bromide by the same procedure as    described in Example 11, (Part A) and N,N-dimethylaniline (0.57 mL,    4.3 mmol) in dichloromethane (3.2 mL) was added powdered AlCl₃ (0.75    g, 5.6 mmol) at room temperature. The reaction mixture was stirred    for 2 h, quenched by addition of 1 N HCl (9.5 mL) and the aqueous    layer was extracted with ethyl acetate. The organics were washed    with brine, dried over anhydrous sodium sulfate and concentrated in    vacuo. The crude product was purified by chromatography on silica    gel, eluting with ethyl acetate/hexane (25:100) to provide the title    compound (0.48 g, 96%) as yellow oil.-   B.    2-Hydroxymethyl-6-[3-(4-methylsulfanyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside:    The title compound was prepared from Part A by the same procedure as    described in Example 11, Part C and D. ¹HNMR (300 MHz, CD₃OD) δ 8    7.22 (d, J=8.30 Hz, 2H), 7.16 (d, J=8.19 Hz, 2H), 6.99–6.97 (m, 2H),    6.72 (s, 1H), 6.69–6.66 (m, 1H), 5.09 (d, J=7.17 Hz, 1H), 4.36 (d,    J=15.9 Hz, 1H), 4.23 (d, J=16.2 Hz, 1H), 3.88 (dd, J=2.17, 12.1 Hz,    1H), 3.66 (dd, J=5.61, 12.0 Hz, 1H), 3.49–3.39 (m, 4H), 2.43 (s,    3H). MS: m/z (MH⁺) 432.

EXAMPLE 28 2-[3-(4-Chloro-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared instep A of Example 1, and 4-chlorophenylmagnesium bromide by the sameprocedure as described in Example 11. ¹HNMR (300 MHz, CD₃COCD₃) δ10.03(br s, 1H), 7.35(d, J=8 Hz, 2H), 7.2(d, J=8 Hz, 2H), 7.1–6.85(m,3H), 6.7(d, J=7 Hz, 1H), 5.11(d, J=7 Hz, 1H), 4.45–4.15(m, 5H),3.95–3.85(m, 1H), 3.75–3.65(m, 1H), 3.6–3.4(m, 5H), 2.93(s, 1H). MS: m/z(M⁺+Na) 442.

EXAMPLE 292-(3-Naphthalen-2-ylmethyl-1H-indol-4-yloxy)-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared instep A of Example 1, and 2-naphthylmethylphenylmagnesium bromide by thesame procedure as described in Example 11. ¹HNMR (300 MHz, CD₃COCD₃) δ10.01(br s, 1H), 7.9–7.8(m, 4H), 7.7.55–7.5(m, 1H), 7.4–7.3(m, 2H),7.05–6.9(M, 2H), 6.85(m, 1H), 7.6(1H), 5.13(d, J=7 Hz, 1H), 4.48(dd,J=15 Hz, 40 Hz, 2H), 3.9–3.8(m, 1H), 3.7–3.45(m, 6H). MS: m/z (M⁺+Na)458.

EXAMPLE 302-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared instep A of Example 1, and 2,3-dihydro-benzofuranylmagnesium bromide bythe same procedure as described in Example 11. ¹HNMR (300 MHz, CD₃OD) δ7.11 (s, 1H), 6.98–6.93 (m, 3H), 6.70–6.58 (m, 3H), 5.08 (d, J=7.31 Hz,1H), 4.47 (t, J=8.66 Hz, 2H), 4.28 (d, J=16.0 Hz, 1H), 4.19 (d, J=16.1Hz, 1H), 3.90–3.85 (m, 1H), 3.71–3.65 (m, 1H), 3.49–3.40 (m, 4H), 3.12(m, 2H). MS: m/z (MH⁺) 428.

EXAMPLE 312-[3-(4-Ethyl-benzyl)-1-isopropyl-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared instep A of Example 1, and 4-ethylphenylmagnesium bromide by the sameprocedure as described in Example 23. ¹HNMR (300 MHz, CD₃OD) δ 7.17 (d,J=8.15 Hz, 2H), 7.07 (d, J=8.16 Hz, 2H), 7.04–7.02 (m, 2H), 6.80 (s,1H), 6.70–6.67 (m, 1H), 5.07 (d, J=7.21 Hz, 1H), 4.60–4.65 (m, 1H), 4.34(d, J=15.9 Hz, 1H), 4.24 (d, J=15.7 Hz, 1H), 3.88 (dd, J=2.16, 12.1 Hz,1H), 3.70–3.64 (m, 1H), 3.54–3.45 (m, 3H), 2.63–2.56 (m, 2H), 2.59 (q,J=7.52 Hz, 2H), 1.21 (t, J=7.54 Hz, 3H). MS: m/z (MH⁺) 456.

EXAMPLE 322-[3-(4-Ethyl-benzyl)-6-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-Benzyloxy-3-formyl-6-methyl-indole-1-carboxylic acid diethylamide(Example 9, Part G) and 4-ethylphenylmagnesium bromide by the proceduredescribed in Example 11. ¹HNMR (300 MHz, CD₃OD) δ 9.8 (br s, 1H), 7.4(d, J=7 Hz, 2H), 7.1 (d, J=7 Hz, 2H), 6.85(s, 1H), 6.75 (s, 1H), 6.55(s, 1H), 5.1–5.05 (m, 1H), 4.25 (dd, J=5 Hz, 10 Hz, 2H), 3.95–3.85 (m,1H), 3.75–3.65 (m, 1H), 3.55–3.3 (m, 4H), 2.55 (q, J=3 Hz, 2H), 2.33(s,3H), 1.20 (t, J=3 Hz, 3H). MS: m/z (M⁺) 427.

EXAMPLE 33 2-[3-(4-Methoxy-phenyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

-   A. 4-Benzyloxy-3-iodo-1H-indole: To a solution of    4-benzyloxy-1H-indole (1.0 g, 4.5 mmol) in pyridine (2.5 mL) was    added dropwise a 1.0 M solution of iodochlororide in dichloromethane    (5 mL, 5 mmol) at 0° C. The mixture was continued to stir at 0° C.    for 15 min, then warmed to room temperature and stirred for 1 h. The    mixture was poured onto ice-water, neutralized with 1 N HCl solution    and extracted with ethyl acetate. The organics were washed with    brine, dried over anhydrous sodium sulfate and concentrated in    vacuo. The residue was crystallized from ethyl acetate/hexane to    give the title compound (1.2 g, 77%) as a light pink solid.-   B. 1-Benzenesulfonyl-4-benzyloxy-3-iodo-1H-indole: A mixture of Part    A (0.35 g, 1 mmol), tetrabutylammonium bromide (0.032 g, 0.1 mmol)    and benzenesulfonyl chloride (0.22 g, 1.3 mmol) in 25% aqueous    sodium hydroxide (2 mL) and benzene (1.6 mL) was stirred at room    temperature overnight. The reaction mixture was quenched by addition    of water and extracted with ethyl acetate. The organic layer was    washed with water and brine, dried over anhydrous sodium sulfate and    concentrated in vacuo. The crude product (0.49 g, 98%, a white    solid) was pure and used directly for the next step.-   C. 1-Benzenesulfonyl-4-benzyloxy-3-(4-methoxy-phenyl)-1H-indole: A    solution of Part B (0.49 g, 1 mmol) in dimethoxyethane (25 mL) was    treated with cesium fluoride (0.46 g, 3 mmol),    4-methoxyphenylboronic acid (0.29 g, 1.5 mmol) and    1,1′-bis-(diphenylphosphino)-ferrocenedichloropalladium (II) (73    mg). The mixture was stirred at 84° C. overnight, cooled to room    temperature, quenched with water and extracted with ethyl acetate.    The organic extracts were dried over anhydrous sodium sulfate,    concentrated in vacuo and chromatographed on silica gel eluting with    ethyl acetate/hexane (30:100) to give the title compound (0.26 g,    55%).-   D. 1-Benzenesulfonyl-3-(4-methoxy-phenyl)-1H-indol-4-ol: A solution    of Part C (0.26 g, 0.55 mmol) in ethanol (5 mL) and ethyl acetate    (10 mL) was hydrogenated over 10% Pd—C (0.05 g) under H₂ (50 psi)    for 6 h. The catalyst was removed by filtration and the filtrate was    concentrated in vacuo. The crude product was purified by    chromatography on silica gel eluting with methanol/chloroform    (4:100) to provide the title compound (0.14 g, 67%) as a yellow    solid.-   E. 2-[3-(4-Methoxy-phenyl)-1H-indol-4-yloxy]-β-D-glucopyranoside:    The title compound was prepared from Part D (0.14 g, 0.36 mmol) by    the same procedure as described in Example 11, Part C and Part D.    ¹HNMR (300 MHz, CD₃OD) δ 7.63–7.60 (m, 2H), 7.15 (s, 1H), 7.10–7.07    (m, 2H), 6.96–6.93 (m, 2H), 6.83–6.80 (m, 1H), 5.07 (d, J=7.25 Hz,    1H), 3.91–3.86 (m, 1H), 3.84 (s, 3H), 3.73–3.67 (m, 1H), 3.44–3.36    (m, 4H). MS: m/z (MH⁺) 402.

EXAMPLE 34 2-[3-Methyl-2-thienyl(-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from4-benzyloxy-3-formyl-indole-1-carboxylic acid diethylamide, prepared instep A of Example 1, and 3-methyl2-thienylmagnesium bromide by the sameprocedure as described in Example 11. ¹HNMR (300 MHz, CD₃OD) δ 7.04 (d,J=5.15 Hz, 1H), 7.02–6.99 (m, 2H), 6.82 (d, J=4.98 Hz, 1H), 6.74–6.69(m, 1H), 6.63 (s, 1H), 5.10 (d, J=7.33 Hz, 1H), 4.44 (d, J=4.72 Hz, 2H),3.90 (dd, J=1.75, 10.35 Hz, 1H), 3.71 (dd, J=5.15, 6.77 Hz, 1H),3.57–3.35 (m, 5H), 2.21 (s, 3H). MS: m/z (MH⁺) 406.

EXAMPLE 352-[3-(4-Pyridin-3-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

-   A. (4-Bromo-phenyl)-(4-methoxy-1H-indol-3-yl)-methanone: To a    mixture of aluminum chloride (7 g, 52.6 mmol) in dichloromethane    (400 mL) was added a solution of 4-methoxyindole (4.0 g, 27.2 mmol)    in dichloromethane (40 mL) dropwise through an addition funnel. The    mixture was stirred at room temperature for 1 h and a solution of    4-bromobenzoylchloride (6 g, 27.2 mmol) in dichloromethane (40 mL)    was slowly added. The resulting mixture was stirred at room    temperature overnight. The mixture was quenched with MeOH and    evaporated to dryness. The residue was diluted with water and    extracted with EtOAc. The organic extracts were washed with brine,    dried over MgSO₄, filtered and evaporated to dryness. The crude    solid product was precipitated with Et₂O and collected by    filtration. The solids were then diluted with MeOH and filtered    washing with several portions of MeOH. The methanolic filtrate was    evaporated in vacuo and chromatographed (EtOAc:Hexane; 1:2) to    afford the title compound (1.0 g, 12%).-   B.    (1-Benzenesulfonyl-4-methoxy-1H-indol-3-yl)-(4-bromo-phenyl)-methanone:    A mixture of the compound prepared in the previous step (1 g, 3.0    mmol), tetrabutylammonium bromide (0.098 g, 0.3 mmol) and 25%    aqueous NaOH (16 mL) in benzene (16 mL) was stirred vigorously    during the addition of sulfonyl chloride (0.75 g, 4.2 mmol). The    resulting mixture was stirred at room temperature overnight, diluted    with H₂O (60 ml) and washed with EtOAc. The organic extracts were    washed with brine, dried over MgSO₄, filtered and evaporated in    vacuo to provide the title compound (1.3 g, 91%).-   C. 1-Benzenesulfonyl-3-(4-bromo-benzyl)-4-methoxy-1H-indole: Sodium    borohydride (2.3 g, 55.3 mmol) was added portionwise over a 30 min    period to trifluoroacetic acid (65 mL) pre-cooled in a flask to    0° C. To this mixture was added a solution of the compound prepared    in Part B (1.3 g, 2.8 mmol) in CH₂Cl₂ (60 mL) through an addition    funnel. The resulting mixture was stirred at room temperature    overnight, cooled in an ice bath and H₂O (100 mL) was added. Sodium    hydroxide (25% solution, 100 mL) was added to a basic pH.    Dichloromethane (150 mL) was added and layers were separated.

The aqueous layer was extracted with CH₂Cl₂. The combined organicextracts were washed with brine, dried over MgSO₄ and evaporated todryness. The crude product was purified by chromatography (Hexane:EtOAc;4:1) to provide the title compound (0.81 g, 60%).

-   D. 1-Benzenesulfonyl-4-methoxy-3-(4-pyridin-3-yl-benzyl)-1H-indole:    A mixture of the compound prepared in Part B (0.45 g, 0.98 mmol),    3-pyridylboronic acid (0.21 g, 1.5 mmol), cesium flouoride (0.45 g,    2.96 mmol) and PdCl₂(dppf)₂ (0.072 g, 0.099 mmol) in ethylene glycol    dimethyl ether (2.5 mL) was stirred at 72° C. for 24 h. The reaction    mixture was cooled to room temperature, diluted with H₂O and EtOAc    and filtered through CELITE™. The filtrate was washed with brine,    dried over MgSO₄, filtered and concentrated in vacuo. The crude    product was purified by chromatography (Hexane; EtOAc; 3:2) to    provide the title compound (0.31 g, 69%).-   E. 1-Benzenesulfonyl-3-(4-pyridin-3-yl-benzyl)-1H-indol-4-ol: A    mixture of the compound (0.31 g, 0.68 mmol), prepared in Part D, in    dichloromethane (20 mL) was cooled to −78° C. and boron tribromide    (1 M solution in CH₂Cl₂; 3.4 mL, 3.4 mmol) was slowly added. The    reaction mixture was stirred at −78° C. for 30 minutes then slowly    warmed up to room temperature and stirred at for 24 h. A 1 M HCl    solution (5 mL) was added dropwise followed by ice H₂O (50 mL). The    methylene chloride was removed under reduced pressure and the    aqueous mixture extracted with EtOAc. The combined EtOAc extracts    was washed with brine, dried over MgSO₄ and concentrated to give the    title compound as a yellow solid (0.20 g, 67%).-   F.    2-[3-(4-Pyridin-3-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside:    To a solution of Part E (0.18 g, 0.41 mmol) in acetone (1 mL) was    added potassium carbonate (0.28 g, 2.1 mmol), followed by addition    of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.34 g, 8.2    mmol). The reaction mixture was stirred at room temperature for 2 h    and another 2 equivalents of    2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide was added. The    mixture was stirred at room temperature for 24 h. Water and EtOAc    were added and the mixture filtered through CELITE™. The filtrate    was washed with water then brine, dried over MgSO₄ and concentrated    in vacuo. The residue was purified by chromatography    (CH₂Cl₂:Acetone; 20:1) to give pure product. This product was    dissolved in EtOH (5 mL) and 50% aqueous KOH (mL) was added. The    mixture was stirred in a 75° C. oil bath for 1 h, H₂O was added and    the aqueous mixture was carefully neutralized with 10% HCl to pH 9.    The EtOH was removed under reduced pressure and the aqueous mixture    extracted with EtOAc. The ethyl acetate solution was washed with    brine, dried over MgSO₄ and concentrated in vacuo. The residue was    purified by chromatography on silica gel eluting with    methanol/chloroform (10:100) to give the title compound (9.1 mg, 30%    yield). ¹HNMR (300 MHz, CD₃OD) δ 8.00 (broad s, 1H), 8.48 (broad s,    1H), 8.06 (d, J=8.25 Hz, 1H), 7.63–7.41 (m, 5H) 7.00 (m, 2H), 6.80    (s, 1H), 6.69–6.67 (m, 1H), 5.10 (d, J=7.2 Hz, 1H), 4.51–4.46 (d,    J=15.9 Hz, 1H), 4.35–4.30 (d, J=15.9 Hz, 1H), 3.89–3.85 (dd, J=12.1    Hz, J=2 Hz, 1H), 3.69–3.63 (dd, J=11.8 Hz, J=5.4 Hz, 1H), 3.54–3.36    (m, 4H). MS: m/z (MH⁺) 463.

EXAMPLE 362-[3-(4-Ethyl-benzyl)-2-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside

-   A. N-(3-Methoxy-2-methyl-phenyl)-acetamide:    1-Methoxy-2-methyl-3-nitro-benzene (0.5 g, 6 mmol) and acetic    anhydride (1.14 g, 12 mmol) were dissolved in 48 mL of acetic acid.    The mixture was hydrogenated over 10% Pd—C (0.12 g) under H₂ (14    psi) for 24 h. The catalyst was removed by filtration and the    filtrate was concentrated in vacuo. The crude product was dissolved    in ethyl acetate and washed with saturated Na₂CO₃ and brine. After    drying with anhydrous sodium sulfate, the solvents were removed and    the product (1.0 g, 99%) was crystallized in diethyl ether as a    white solid.-   B. 4-Methoxy-2-methyl-1H-indole: A mixture of Part A (0.72 g, 4    mmol) and sodium amide (0.39 g, 10 mmol) in N,N-diethylaniline (1    mL) was heated to 210° C. over the period of 30 mins. The mixture    was stirred at 210° C. for 20 mins, cooled to 90° C., and decomposed    with ethanol (0.5 mL) and water (1.5 mL). After cooling to room    temperature, the aqueous phase was extracted with diethyl ether. The    organic extracts were dried over anhydrous sodium sulfate,    concentrated in vacuo and purified by chromatography on silica gel    eluting with ethyl acetate/hexane (10:100) to give the title    compound (0.19 g, 30%).-   C. 3-(4-Ethyl-benzyl)-4-methoxy-2-methyl-1H-indole: A solution of    Part B (0.19 g, 1.17 mmol) and 4-ethylbenzaldehyde (0.20 g, 1.5    mmol) in dichloromethane (6 mL) was added in drops to a solution of    TFA (0.2 g, 1.8 mmol) and triethylsilane (0.41 g, 3.51 mmol) in    dichloromethane (2 mL). The reaction was monitored by TLC until    judged complete (20 mins) then basified to pH 8–9 with NaOH (1M) and    partitioned between dichloromethane and brine. The organic extracts    were dried over anhydrous sodium sulfate, concentrated in vacuo and    purified by chromatography on silica gel eluting with    chloroform/hexane (20:100) to give the title compound (0.20 g, 61%).-   D.    1-Benzenesulfonyl-3-(4-ethyl-benzyl)-4-methoxy-2-methyl-1H-indole: A    mixture of the compound as prepared in Part C (0.25 g, 0.9 mmol),    tetrabutylammonium bromide (0.032 g, 0.1 mmol) and benzenesulfonyl    chloride (0.22 g, 1.3 mmol) in 25% aqueous sodium hydroxide (2 mL)    and benzene (2 mL) was stirred at room temperature overnight. The    reaction mixture was quenched by addition of water and extracted    with ethyl acetate.

The organic layer was washed with water and brine, dried over anhydroussodium sulfate and concentrated in vacuo. The crude product was purifiedby chromatography on silica gel eluting with chloroform/hexane (10:100)to give the title compound (0.10 g, 27%) as yellow oil.

-   E. 1-Benzenesulfonyl-3-(4-ethyl-benzyl)-2-methyl-1H-indol-4-ol: To a    solution of Part D (0.10 g, 0.24 mmol) in dichloromethane (5 mL) was    added a 1.0 M solution of boron tribromide (1 mL, 1 mmol) at −78° C.    The reaction mixture was stirred at −78° C. for 30 minutes then    slowly warmed up to room temperature and stirred at for 24 h. A 1 M    HCl solution (1 mL) was added dropwise followed by ice H₂O (10 mL).    The methylene chloride was removed under reduced pressure and the    aqueous mixture extracted with EtOAc. The combined organic extracts    was washed with brine, dried over sodium sulfate and concentrated.    The crude product was purified by chromatography on silica gel    eluting with ethyl acetate/hexane (25:100) to give the title    compound (0.06 g, 64%) as a light brown solid.-   F.    2-[3-(4-Ethyl-benzyl)-2-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside:

The title compound was prepared from Part E as described in Example 11,Part C and D. ¹HNMR (300 MHz, CD₃OD) δ 7.11 (d, J=8.06 Hz, 2H), 7.02 (d,J=7.92 Hz, 2H), 6.95–6.90 (m, 2H), 6.63 (dd, J=7.36, 1.06 Hz, 1H), 5.04(d, J=7.50 Hz, 1H), 4.38 (d, J=16.0 Hz, 1H), 4.14 (d, J=17.0 Hz, 1H),3.86 (dd, J=2.15, 12.0 Hz, 1H), 3.65 (dd, J=5.70, 12.1 Hz, 1H),3.44–3.36 (m, 4H), 2.56 (q, J=7.38 Hz, 2H), 2.29 (s, 3H), 1.18 (t,J=7.66 Hz, 3H). MS: m/z (MH⁺) 414. MS: m/z (MH⁺) 428.

EXAMPLE 372-[3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared as described in Example 35 substitutingthe 3-pyridylboronic acid in Part D with 3-thiophinylboronic acid. ¹HNMR(300 MHz, CD₃OD) δ 7.58–7.55 (m, 3H), 7.48–7.45 (m, 2H), 7.34 (m, 2H),7.05–7.01 (m, 2H), 6.79 (s, 1H), 6.73–6.70 (m, 1H), 5.12 (d, J=7.06 Hz,1H), 4.47–4.29 (dd, J=15.98 Hz, 2H), 3.93–3.88 (m, 1H), 3.73–3.35 (m,5H). MS: m/z (MH⁺) 468.

EXAMPLE 38 2-[3-(4-Ethylbenzoyl)-1H-indol-4-yloxy]-β-D-glucopyranoside

-   A. (4-Ethyl-phenyl)-(4-methoxy-1H-indol-3-yl)-methanone: To a    mixture of aluminum chloride (0.18 g, 1.36 mmol) in dichloromethane    (15 mL) was added a solution of 4-methoxyindole (2.0 g, 13.6 mmol)    in dichloromethane (10 mL) dropwise. The mixture was stirred at room    temperature for 0.5 hr and a solution of 4-Ethylbenzoylchloride    (2.29 g, 13.6 mmol) was slowly added. The resulting mixture was    stirred at room temperature overnight. The mixture was quenched with    water and extracted with EtOAc (3×50 mL). The organic extracts were    washed with brine, dried over MgSO₄, filtered and evaporated to    dryness. The crude product was purified by chromatography (silica    gel, hexane/EtoAc, 4:1) to provide the title compound (0.24 g, 6%).-   B. 3-(4-Ethylbenzoyl)-1H-indol-4-ol: To a solution of Part A (0.29    g, 1.04 mmol) in dichloromethane (10 mL) was added a 1.0 M solution    of boron tribromide (3.8 mL, 4.16 mmol) at −78° C. The reaction    mixture was stirred at −78° C. for 30 minutes then slowly warmed up    to room temperature and stirred at RT for 24 h. A 1 M HCl solution    (10 mL) was added dropwise followed by ice H₂O (10 mL). The    methylene chloride was removed under reduced pressure and the    aqueous mixture extracted with EtOAc (3×50 mL). The combined organic    extract was washed with brine, dried over sodium sulfate and    concentrated. The crude product was washed with ether and filtered.    The ether solution was evaporated to dryness to give the title    compound (0.085 g, 30%).-   C. 2-[3-(4-Ethylbenzoyl)-1H-indol-4-yloxy]-β-D-glucopyranoside: To a    solution of Part B (0.08 g, 0.302 mmol) in MeOH (5 mL) was added    lithium hydroxide (0.08 g, 3.32 mmol) and the solution was stirred    at RT. After 5 min, the solution was evaporated to dryness.    2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.62 g, 1.51    mmol) was added after diluting the residue in DMF (5 mL). After    stirring the reaction mixture at RT overnight, potassium carbonate    (0.41 g, 2.97 mmol) and MeOH (5 mL) was added and stirred at RT    overnight. The resulting solution was poured into water (20 mL) and    the product was extracted with EtOAc (3×50 mL), ether was added and    the organic extract was washed with water (4×50 mL) and brine. The    combined extract was dried over MgSO₄, filtered and concentrated in    vacuo.

The residue was purified by chromatography (silica gel,dichloromethane:methanol, 97:3) to give the title compound (0.008 g, 6%)as a white solid. 1 HNMR (300 MHz, CD3OD) δ 7.95 (s, 1H), 7.78 (d,J=8.09, 2H), 7.40 (d, J=7.89, 2H), 7.19 (m, 2H), 6.65 (d, J=7.47, 1H),5.47 (d, J=9.09, 1H), 3.80 (m, 4H), 3.54 (m, 2H), 2.77 (q, J=7.47, 2H),1.30 (t, J=7.59, 3H). MS: m/z (MH⁺) 428.

-   F. Biological Examples.

EXAMPLE 1 Materials and Methods

Cloning of the human SGLT1 and human SGLT2 cDNAs and construction of themammalian expression vector: The human SGLT1 cDNA (Genbank M24847) wascloned from human small intestine. Human SGLT2 cDNA (Genbank M95549) wascloned from human kidney. Both full cDNAs were subcloned into pcDNA andsequenced to verify the integrity of the construct. Generation of CHO-K1cells stably expressing human SGLT1 or human SGLT2: Transfection ofCHO-K1 cells was performed using DMRIE-C reagent (Life Technologies,Gaithersburg, Md.). Transfectants were then selected in the presence ofthe antibiotic G418 (Gibco-BRL, Grand Island, N.Y.) at 400 μg/ml.Individual clones were then characterized using the functional assaydescribed below.

Cell-based assay for sodium-dependent glucose transport: Cell linesstably expressing human SGLT1 or SGLT2 were then used for functionalanalysis of Na+-dependent glucose uptake. Briefly, cells were plated ata density of 65,000 cells per well in a 96-well plate and allowed togrow for 48 hours. Cells were subsequently washed one time with AssayBuffer (50 mM HEPES pH 7.4, 20 mM Tris, 5 mM KCl, 1 mM MgCl₂, 1 mM CaCl₂and 137 mM NaCl) and treated with compound in the absence or presence ofNaCl for 15 minutes. Cells were then labeled with¹⁴C-α-methylglucopyranoside (AMG, Sigma, St. Louis, Mo.), anon-metabolizable glucose analog specific for sodium-dependent glucosetransporters as previously described (Peng, H. and Lever J. E.Post-transcriptional regulation of Na⁺/glucose cotransporter (SGLT1)gene expression in LLC-PK1 cells. J Biol Chem 1995;270:20536–20542.).After 2 hours the □abeled cells were washed three times with ice-coldPBS. After aspiration, cells were solubilized using Microscint 20(Packard, Meriden, Conn.) and Na-dependent ¹⁴C-AMG uptake was quantifiedby measuring radioactivity. Plates were counted in a TopCount (Packard,Meriden, Conn.). Results are reported as the % inhibition or IC50 valuefrom a representative experiment. Variability for the functional assaywas typically within 20%.

EXAMPLE 2 In Vivo Assay for Efficacy

Male Zucker Diabetic Fatty (ZDF) rats (7–8 weeks) were obtained fromCharles River. Animals were maintained on a 12-hour light/dark cycle ina temperature-controlled room. Animals were given ad libitum access tofood (standard rodent diet Purina 5008) and water. Animals were fastedfor 12 hours prior to initiation of the experiment. On the morning ofthe experiment, animals were administered vehicle (0.5% methylcellulose)or compound by oral gavage (1 ml/kg). After one hour, animals receivedan oral glucose challenge (4 ml/kg of 50% solution) and were immediatelyplaced in metabolism cages. Animals were given free access to water andurine was collected for 4 hours. Urinary glucose was quantified usingthe Trinder Reagent (Sigma).

EXAMPLE 3 Effects on Plasma Glucose, Plasma Insulin, PlasmaTriglycerides, Plasma Free Fatty Acids, Liver Weight, and Body Weight

To examine the effect of an SGLT inhibitor in combination with an RXRagonist, female db/db mice (6–7 weeks of age/Jackson Labs, ME) aretreated daily for 11 days with vehicle (0.5% methylcellulose), an RXRagonist (0.1–10 mpk (mg/kg)), an SGLT inhibitor (100 mpk), or an RXRagonist plus SGLT inhibitor. Mice (n=8 animals/group) receive the testcompounds or vehicle by oral gavage in a volume of 10 ml/kg of bodyweight. Body weight is recorded on day 1, prior to dosing, and days 4, 8and 11. Eighteen hours after the final dose, mice are weighed andanesthetized with CO₂/O₂ (70:30). Mice are then bled by retro-orbitalsinus puncture into 2 mL heparinized polypropylene tubes on ice. Plasmasamples are then assayed for glucose, insulin, triglycerides, and freefatty acids. Livers are excised, weighed and frozen.

The SGLT inhibitors and RXR agonists have distinct mechanisms of action.Improved glycemic control, measured as a decrease in plasma glucose,plasma insulin, plasma free fatty acids, or plasma triglycerides, or acombination thereof, can be observed at lower concentrations of an RXRagonist when given in combination with an SGLT inhibitor. Therefore, aleftward shift in the dose-response curve for effect of an RXR agoniston the above parameters can become apparent. In addition, the weightgain observed following treatment with RXR agonists is less pronouncedwhen given with the SGLT inhibitor, since SGLT inhibitors' promotion ofthe urinary excretion of glucose and loss of calories from the body isdemonstrated by reduction in weight or weight gain. Also, since SGLTinhibitors promote a mild diuresis, the edema (and the edematous weightgain) commonly observed after treatment with RXR agonists can be lesspronounced or absent. A reduction in the amount of an RXR agonistnecessary to achieve efficacy in turn improves the side-effect profile.The decreased side effects can include such conditions as fatty liver,increased liver weight, body weight gain, heart weight gain, edema,cardiac hypertrophy, hepatohypertrophy, hypoglycemia, andhepatotoxicity, or any combination thereof.

EXAMPLE 4 Effects on Plasma Glucose, HbA1c, Hematocrit, Plasma Insulin,Plasma Triglycerides, Plasma Free Fatty Acids, Total Cholesterol, HDL,Plasma Drug Levels, Liver Weight, Heart Weight, Fat Content and BodyWeight

To examine the effect of an SGLT inhibitor in combination with an RXRagonist, male ZDF rats (6 weeks of age/GMI) are treated daily for 28days with vehicle (0.5% methylcellulose), an RXR agonist (0.1 mpk–10mpk), SGLT inhibitor (3–100 mpk), or an RXR agonist plus SGLT inhibitor.Rats (n=8 animals/group) receive the test compounds or vehicle by oralgavage in a volume of 2 ml/kg of body weight. Body weight is recorded onday 1, prior to dosing, and twice a week for the duration of the study.On the day prior to the final dose, animals are fasted overnight. Onehour after the final dose, rats are weighed and anesthetized with CO₂/O₂(70:30). Rats are then bled by retro-orbital sinus puncture into 2 mLheparinized polypropylene tubes on ice. Rats then receive a glucosechallenge (2 g/kg p.o) and are placed in metabolism cages for the urinecollection (4 hours). Animals are then sacrificed and epididymal fatpads, livers, and hearts are excised, weighed and frozen forhistological examination. Plasma samples are then assayed for glucose,HbA1c, insulin, hematocrit, plasma drug levels, total cholesterol, HDL,free fatty acids, and triglycerides. Urine volume and urinary glucose,protein, osmolarity, electrolytes (Na, K, Cl), BUN and creatinine aremeasured.

The SGLT inhibitors and RXR agonists have distinct mechanisms of action.Improved glycemic control, measured as a decrease in plasma glucose,HbAlc, plasma insulin, or plasma triglycerides, or a combinationthereof, can be observed at lower concentrations of RXR agonists whengiven in combination with an SGLT inhibitor. Therefore, a leftward shiftin the dose-response curve for effect of RXR agonists on the aboveparameters can become apparent. In addition, the weight gain observedfollowing treatment with RXR agonists is less pronounced when given withthe SGLT inhibitor, since SGLT inhibitors' promotion of the urinaryexcretion of glucose and loss of calories from the body is demonstratedby reduction in weight or weight gain. Also, since SGLT inhibitorspromote a mild diuresis, the edema (and the edematous weight gain)commonly observed after treatment with RXR agonists can be lesspronounced or absent. This can be demonstrated by a reduction in the RXRagonist-induced increase in heart weight. A reduction in the amount ofRXR agonists necessary to achieve efficacy in turn improves theside-effect profile. The decreased side effects can include suchconditions as fatty liver, increased liver weight, body weight gain,heart weight gain, edema, cardiac hypertrophy, hepatohypertrophy,hypoglycemia, and hepatotoxicity, or any combination thereof.

The above examples can also show that the oral administration of anSGLTinhibitor in combination with an antidiabetic agent such as an RXRmodulator improve the status of other markers of diabetes mellitusincluding glycosylated hemoglobin (Hgb A1C) levels. Particularly, theoral administration of an SGLT inhibitor in combination with one or moreantidiabetic agents can reduce body weight or body weight gain as wellas liver weight or liver weight gain, compared to administration of oneor more antidiabetic agents alone.

Thus, for treating diabetes, particularly Type II diabetes mellitus, orSyndrome X, a compound of Formula (I) in combination with one or moreantidiabetic agents that increases insulin sensitivity, may be employedcomprising administering repeated oral doses of the compound of formulaI in the range of about 25 to 1000 mg once or twice daily and repeateddoses of the anti-diabetic agent or agents at jointly effective dosages.The jointly effective dosage for antidiabetic agents such as RXRagonists disclosed herein may be readily determined by those skilled inthe art based on standard dosage guidelines. In particular, suchcombined administration can be effective to accomplish reduction of bodyweight, body weight gain, liver weight, or liver weight gain in thesubject.

Additionally, a method comprising (a) administering to a subject ajointly effective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of anantidiabetic agent can be used to reduce body weight, body weight gain,or liver weight of the subject in need thereof, wherein the combinedadministration can be in any order and the combined jointly effectiveamounts provide the desired therapeutic effect.

Also, a method comprising (a) administering to a subject a jointlyeffective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of anantidiabetic agent can be used to control body weight, body weight gain,liver weight, or liver weight gain of the subject having diabetes,Syndrome X, or associated symptoms or complications, wherein thecombined administration can be in any order and the combined jointlyeffective amounts providing the desired therapeutic effect.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient's sex, age,weight, diet, time of administration and concomitant diseases, willresult in the need to adjust dosages.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

TABLE 3 CHOK-SGLT1 CHOK-SGLT2 Example # IC50 (uM) IC50 (uM) 1 0.1480.020 3 0.195 0.062 4 0.823 0.098 5 3.38 0.146 6 1.06 0.149 7 0.56 0.14210 2.73 0.376 8 1.34 0.183 9 46% Inh. @ 10 μM 50% Inh. @ 1 μM  22 1.120.118 23 69% Inh. @ 10 μM 1.22  24 79% Inh. @ 10 μM 0.202 27 1.31 0.02625 49% Inh. @ 10 μM 0.100 15 3.88 0.053 16 42% Inh. @ 3 μM 0.067 11 1.810.024 12 0 0.66  13 0 0.65  14 71% Inh. @ 10 μM 0.206 32 30% Inh. @ 10μM 0.117 31 0 5.11  17 3.2 0.049 18 49% Inh. @ 10 μM 0.088 19 63% Inh. @10 μM 0.101 20 35% Inh. @ 10 μM 0.114 35 1.12 0.133 26 0 0.42  28 58%Inh. @ 10 μM 0.346 34 27% Inh. @ 10 μM 5.04  29 68% Inh. @ 10 μM 0.26 30 30% Inh. @ 10 μM 1.87  33 0 37% Inh. @ 10 μM 2 1.36 0.158 21 43% Inh.@ 10 μM 1.43  36 16% Inh. @ 10 μM 52% Inh. @ 10 μM 37 1.89 0.034 38  7%Inh. @ 10 μM 22% Inh. @ 10 μM

1. A compound of formula (I)

wherein R₁ is H, C₁₋₄ alkyl, or R₄R₅N—(CO)—; each of R₄ and R₅ isindependently C₁₋₅ alkyl; R₂ is H, F, Cl or C₁₋₄ alkyl; R₃ is H or C₁₋₄alkyl, provided that where R₃ is C₁₋₄ alkyl, then R₂ is H; Q is —C(O)—,or —(CH₂)_(n)— where n=0, 1, or 2; P═H, C₁₋₇ acyl, or (C₁₋₆alkoxy)carbonyl; Z is substituted or unsubstituted, and is selected fromC₃₋₇ cycloalkyl, phenyl, 5- or 6-membered heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, a biaryl, a 9- or10-membered fused bicyclyl or fused heterobicyclyl, wherein said fusedheterobicyclyl has between 1 and 4 heteroatoms independently selectedfrom N, O, and S; or a pharmaceutically acceptable salt, thereof.
 2. Acompound of claim 1, wherein R₁ is H.
 3. A compound of claim 1, whereinR₂ is H, methyl, or ethyl.
 4. A compound of claim 1, wherein Q is—(CH₂)_(n)— and n is 1 or
 2. 5. A compound of claim 1, wherein Z isunsubstituted or independently substituted with between 1 and 3substituents independently selected from C₁₋₄ alkoxy, phenoxy, C₁₋₄alkyl, C₃₋₆ cycloalkyl, halo, hydroxy, cyano, amino, C₁₋₄ alkylthio,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl, C₁₋₄ aminoalkyl, mono and di(C₁₋₄ alkyl)amino, phenyl, C₁₋₄ alkylaminosulfonyl (SO₂NHR), amino (C₁₋₄alkylsulfonyl) (NHSO₂R), di C₁₋₄ alkylaminosulfinyl (SONHRR), C₁₋₄alkylamido (NHCOR), C₁₋₄ alkylcarbamido (CONHR), and 5–6 memberedheterocyclyl containing between 1 and 3 heteroatoms independentlyselected from N, S, and O; and wherein the substituent(s) on Z can befurther independently substituted with between 1 and 3 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ alkyl, halo, hydroxy,cyano, amino, mono- or di C₁₋₄ alkylamino and C₁₋₄ alkylthio.
 6. Acompound of claim 1, wherein Z is selected from 4-substituted phenyl,3,4-disubstituted phenyl, benzhydryl, substituted or unsubstitutedthiophene, biaryl, benzofuranyl, dihydrobenzofuranyl, 4-substitutedpyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl, indanyl, andnaphthyl.
 7. A compound of claim 5, wherein Z is unsubstituted orsubstituted with between 1 and 2 substituents independently selectedfrom methoxy, ethoxy, fluoro, chloro, methyl, ethyl, propyl, butyl andisopropyl.
 8. A compound of claim 1, wherein Z is biphenyl,4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl, 4-(1H-pyrazol-1-yl)phenyl,2-(5-phenyl)thiophenyl, (4-ethyl)phenyl, (4-propyl)phenyl,(4-methoxy)phenyl, dihydrobenzofuran-5-yl, or dihydrobenzofuran-6-yl. 9.A compound of claim 1, wherein R₁ is H; and R₂ is H, methyl, ethyl,propyl, or isopropyl.
 10. A compound of claim 1 wherein Q is—(CH₂)_(n)—; n is 1 or 2; and R₂ is H, methyl or ethyl.
 11. A compoundof claim 1, wherein P is H, C₁₋₃ acyl, or (C₁₋₃ alkoxy)carbonyl.
 12. Acompound of claim 2, wherein R₁ is H; R₂ is H, methyl, or ethyl; Q is—(CH₂)_(n)— and n is 1 or 2; and Z is 4-substituted phenyl,3,4-disubstituted phenyl, benzhydryl, substituted or unsubstitutedthiophene, biaryl, benzofuranyl, dihydrobenzofuranyl, 4-substitutedpyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl, indanyl, andnaphthyl.
 13. A compound of claim 1 wherein R₁ is H; R₂ is H, methyl, orethyl; wherein Z is 4-substituted phenyl, 3,4-disubstituted phenyl,benzhydryl, substituted or unsubstituted thiophene, biaryl,benzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl,benzo[b]thienyl, chromanyl, benzothiophenyl, indanyl, and naphthyl; andZ is unsubstituted or substituted with between 1 and 2 substituentsindependently selected from methoxy, ethoxy, fluoro, chloro, methyl,ethyl, propyl, butyl and isopropyl.
 14. A compound of claim 1, selectedfrom2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1-methyl-1H-indol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Methoxy-phenyl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-methoxycarbonyl-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-hexanoyl-β-D-glucopyranoside;2-[3-(4-Methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-(3-Biphenyl-4-ylmethyl-1H-indol-4-yloxy)-β-D-glucopyranoside;2-[3-(4-Ethoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methylsulfanyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside; and2-[3-(4-Pyridin-3-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside. 15.A compound of claim 1, selected from2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-6-O-acetyl-β-D-glucopyranoside;2-[3-(2-Benzo[1,3]dioxol-5-yl-ethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[3-(2-Naphthalen-2-yl-ethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(4-Ethoxy-phenyl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Methoxy-phenyl)-ethyl]-6-methyl-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[3-(3-Fluoro-4-methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Propyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Isopropyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(2-Fluoro-biphenyl-4-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(3-Fluoro-4-methoxy-benzyl)-1H-indol-4-yloxy]-D-glucopyranoside;2-[3-(4-Phenoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Chloro-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-(3-Naphthalen-2-ylmethyl-1H-indol-4-yloxy)-β-D-glucopyranoside and2-[3-(4-Ethyl-benzyl)-2-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside.16. A compound of claim 1, selected from2-{3-[2-(4-Ethyl-phenyl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[1-Diethylcarbamoyl-3-(4-methoxy-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methoxy-benzyl)-1-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1-isopropyl-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-Methyl-2-thienyl(-1H-indol-4-yloxy)-β-D-glucopyranoside;2-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranosideand 2-[3-(4-Ethylbenzoyl)-1H-indol-4-yloxy]-β-D-glucopyranoside and2-[3-(4-Methoxy-phenyl)-1H-indol-4-yloxy]-β-D-glucopyranoside.
 17. Acompound from claim 1, selected from2-[3-(4-Cyclopropyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Pyrazol-1-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[6-Chloro-3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-fluoro-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(5-Ethyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(5-Propyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;and2-[3-(5-Phenyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside.18. A compound from claim 1, selected from:2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1-methyl-1H-indol-4-yloxy}-β-D-glucopyranoside;2-[3-(3-Fluoro-4-methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methylsulfanyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-methoxycarbonyl-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-β-D-glucopyranoside;2-[3-(4-Propyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-(3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy)-β-D-glucopyranoside;2-[3-(4-Cyclopropyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Pyrazol-1-yl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside,2-[6-Chloro-3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-fluoro-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(5-Ethyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranosideand2-[3-(5-Phenyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-β-D-glucopyranoside.19. A compound in claim 1, selected from2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-β-D-glucopyranoside;and 2-(3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy)-β-D-glucopyranoside.20. A pharmaceutical composition, comprising a compound of claim 1, 5,6, 11, 12, 14, 15, 16, 17, 18 or
 19. 21. A pharmaceutical composition,comprising a compound selected from claim 18 or 19.